Pyrazole derivative, medicinal composition containing the same, medicinal use thereof and intermediate in producing the same

ABSTRACT

The present invention provides pyrazole derivatives represented by the general formula:  
                 
 
wherein R 1  represents H, an optionally substituted C 1-6  alkyl group etc.; one of Q and T represents a group selected from the following groups:  
                 
 
and the other represents —(CH 2 ) n —Ar wherein Ar represents an optionally substituted C 6-10  aryl group or an optionally substituted C 1-9  heteroaryl group; and n represents an integral number from 0 to 2, an optionally substituted C 1-6  alkoxyl group, an optionally substituted amino group, an optionally substituted C 2-9  heterocycloalkyl group or an optionally substituted heterocycle-fused phenyl group; R represents an optionally substituted C 3-8  cycloalkyl group, an optionally substituted C 6-10  aryl group etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human 1,5-anhydroglucitol/fructose/mannose transporter and are useful as agents for the prevention, inhibition of progression or treatment of a disease associated with the excess uptake of at least a kind of carbohydrates selected from glucose, fructose and mannose or a disease associated with hyperglycemia (e.g., diabetic complications, diabetes, etc.), and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.

TECHNICAL FIELD

The present invention relates to pyrazole derivatives, pharmaceuticallyacceptable salts thereof or prodrugs thereof which are useful asmedicaments, pharmaceutical compositions comprising the same,pharmaceutical uses thereof and intermediates for production thereof.

More particularly, the present invention relates to pyrazole derivativeshaving an inhibitory activity to a cotransporter of glucose,1,5-anhydroglucitol, fructose and mannose coupled with sodium(hereinafter referred to as 1,5-anhydroglucitol/fructose/mannosetransporter), pharmaceutically acceptable salts thereof or prodrugsthereof which are useful as agents for the prevention, inhibition ofprogression or treatment of diseases associated with the excess uptakeof at least a kind of carbohydrates selected from glucose, fructose andmannose such as diabetic complications and diabetes, pharmaceuticalcompositions comprising the same, pharmaceutical uses thereof andintermediates for production thereof.

BACKGROUND ART

Glucose, one of the most important energy sources for body, is taken upinto a cell across cell membrane to be made available in the body. Amembrane protein called glucose transporter is involved in this uptakeat cell membrane. Glucose transporter is classified into two maincategories of facilitated glucose transporter which uptakes glucosedepending on intracellular and extracellular glucose concentrationdifference, and sodium/glucose cotransporter (SGLT) which uptakesglucose by using intracellular and extracellular ion concentrationdifference (for example, see the following Reference 1). Regarding SGLT,it has been known that SGLT1, sodium/glucose cotransporter having a highaffinity, mainly exists in the small intestine, and SGLT2,sodium/glucose cotransporter having a low affinity, mainly exists inrenal tubule (for example, see the following References 2 and 3). Inaddition, SGLT3, a human homologue of pig sodium/glucose cotransporterwith a low affinity, pSAAT (for example, see the following Reference 4)was reported (for example, see the following Reference 5). Thus, SGLTsare involved in glucose absorption in the small intestine and glucosereabsorption in the kidney (for example, see the following Reference 6).Therefore, a SGLT inhibitor is expected to lower blood glucose level bysuppressing the intestinal glucose absorption and accelerating glucoseexcretion into urine. Actually, as a result of a study using phlorizinknown as a SGLT inhibitor, it was confirmed that by inhibiting SGLTurinary glucose excretion increased, blood glucose level lowered andinsulin resistance was improved (for example, see the followingReferences 7 and 8). In these years, various SGLT inhibitors has beenfound and are currently under development as treatment agents fordiseases associated with glucose, lipid and energy metabolism includingdiabetes (for example, see the following References 9-12).

In these years, a gene that codes for a protein having a sodium/glucosecotransporting activity was newly reported (see the following Reference13) and applied for a patent (Japan Patent Application no.2002-88318).The protein of the Japan patent application no.2002-88318 (hereinafterreferred to as SMINT) has 7 amino-acid residues (Met Ser Lys Glu Leu AlaAla) at N-terminal extended from a protein described in the Reference 13(hereinafter referred to as SGLTh). The both proteins share high DNA andamino-acid sequence homology with SGLT1 and SGLT2, and mammalian cellsbeing expressed these genes show an activity of the sodium-dependentsugar uptake. Therefore, the both are considered as a member of SGLTfamily.

Among these SGLTs, SGLT1 is known to transport galactosein addition toglucose (for example, see the following Reference 14), while SGLT2 andSGLT3 have low abilities transporting sugars other than glucose (forexample, see the following References 4 and 15). However, thecharacteristics of SMINT and SGLTh in transporting sugars have not beenunderstood at all.

It has been known that blood mannose level increases in diabetes (forexample, see the following Reference 16). In addition, it is known thatblood mannose level has a positive correlation with blood glucose leveland triglyceride level and a negative correlation with HDL cholesterolin metabolic syndrome (for example, see the following Reference 17). Onthe other hand, it is known that fructose consumes a lot of ATP throughthe intracellular metabolic pathway and forms lactose, and that causes aso-called fructose toxicity (for example, see the following Reference18). Mannose and fructose are known to accumulate in renal glomerulus indiabetic rats, and their relations with diabetic nephropathy have beenpointed out (for example, see the following Reference 19). Moreover, ithas been reported that mannose and fructose have a protein glycationability more than 5-times as glucose in glycation reaction with proteinsconsidered as a cause of diabetic complications (for example, see thefollowing Reference 20). Furthermore, it was reported that1,5-anhydroglucitol/fructose/mannose transporter exists functionally inthe kidney, etc. (for example, see the following References 21 and 22).Therefore, as the inhibitory effects on the excess consumption offructose and mannose as well as glucose in the body are expected to bedesirable for the prevention, inhibition of progression or the like ofdiabetic complications, especially including diabetic nephropathy, ithas been desired to early develop an agent having such an inhibitoryeffect.

Although various compounds having a pyrazole structure like the presentinvention are known, these compounds are SGLT1 or SGLT2 inhibitors, orSGLT inhibitors which have excreting effects of urinary glucose.Therefore, it has not been known that pyrazole derivatives of thepresent invention have an inhibitory effect on1,5-anhydroglucitol/fructose/mannose transporter activity, exert aninhibitory effect on uptake of carbohydrates such as glucose, fructoseand mannose, and are useful for the prevention, inhibition ofprogression or treatment of diseases associated with excess uptake of atleast a kind of carbohydrates selected from glucose, fructose andmannose (for example, see the following References 23-31).

Reference 1: Graeme I. Bell and 7 persons, Diabetes Care, March 1990,Vol.13, No.3, pp.198-208;

Reference 2: Matthias A. Hediger and 2 persons, Proc. Natl. Acad. Sci.USA, August 1989, Vol.86, pp.5748-5752;

Reference 3: Rebecca G. Wells and 5 persons, Am. J. Physiol., September1992, Vol.263, pp.F459-465;

Reference 4: Bryan Mackenzie and 4 persons, J. Biol. Chem., September1994, Vol.269, No.36, pp.22488-22491;

Reference 5: GenBank Data Bank, online, search held on Mar. 11, 2002,Accession No.AJ133127;

Reference 6: Bernard Thorens, Am. J. Physiol., April 1996, Vol.270,pp.G541-G553;

Reference 7: Luciano Rossetti and 4 persons, J. Clin. Invest., May 1987,Vol.79, pp.1510-1515;

Reference 8: Barbara B. Kahn and 4 persons, J. Clin. Invest., February1991, Vol.87, pp.561-570;

Reference 9: International Publication no.WO01/27128;

Reference 10: Kenji Arakawa and 7 persons, Br. J. Pharmacol., January2001, Vol.132, No.2, pp.578-586;

Reference 11: Masayuki Isaji and 8 persons, FASEB J., March 2001,Vol.15, No.4, p.A214;

Reference 12: Kenji Katsuno and 7 persons, FASEB J., March 2001, Vol.15,No.4, p.A214;

Reference 13: International Publication no.WO02/053738;

Reference 14: E. Turk and 4 persons, Nature, March 1991, Vol.350,No.6316, pp.354-356;

Reference 15: Yoshikatsu Kanai and 4 persons, J. Clin. Invest., January1994, Vol.93, pp.397-404;

Reference 16: Elja Pitkanen, Clin. Chim. Acta, July 1996, Vol.251, No.1,pp.91-103;

Reference 17: 0. M. Pitkanen and 2 persons, Scand J. Clin. Lab. Invest.,December 1999, Vol.59, No.8, pp.607-612;

Reference 18: R. Gitzelmann and 2 persons, The Metabolic and MolecularBases of Inherited Disease, McGraw-Hill in the US, 1995, pp.905-934;

Reference 19: Li Ning Wang and 3 persons, The Japanese Journal ofNephrology, 1990, Vol.32, No.4, pp.401-408;

Reference 20: H. Franklin Bunn and 1 person, Science, July 1981,Vol.213, pp.222-224;

Reference 21: Toshikazu Yamanouchi and 5 persons, Biochim. Biophys.Acta., August 1996, Vol.1291, No.1, pp.89-95;

Reference 22: T. Blasco and 5 persons, J. Membr. Biol., November 2000,Vol.178, No.2, pp.127-135;

Reference 23: International Publication no.WO01/16147;

Reference 24: International Publication no.WO02/05373;

Reference 25: International Publication no.WO02/068439;

Reference 26: International Publication no.WO02/068440;

Reference 27: International Publication no.WO03/098893;

Reference 28: International Publication no.WO03/020737;

Reference 29: International Publication no.WO02/36602;

Reference 30: International Publication no.WO02/088157;

Reference 31: Japan Patent Publication no.JP2003-12686.

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly on human SMINT. As aresult, it was found that the human SMINT of the Japanese patentapplication no.2002-88318 exists highly in the kidney and smallintestine and characteristically transports 1,5-anhydroglucitol,fructose and mannose besides glucose, and human SMINT functions as a1,5-anhydroglucitol/fructose/mannose transporter. That is, it was foundthat the excess uptake of glucose, fructose and mannose can be inhibitedby inhibiting 1,5-anhydroglucitol/fructose/mannose transporter, and aninhibitor of 1,5-anhydroglucitol/fructose/mannose transporter is usefulfor the prevention, inhibition of progression or treatment of diabetes,diabetic complications including diabetic nephropathy and the like.Therefore, the present inventors have studied earnestly to find acompound which exerts an inhibitory effect on1,5-anhydroglucitol/fructose/mannose transporter. As a result, it wasfound that certain pyrazole derivatives represented by the followinggeneral formula (I) show an excellent inhibitory activity on1,5-anhydroglucitol/fructose/mannose transporter as shown below, therebyforming the basis of the present invention.

The present invention is to provide novel compounds which is useful forthe prevention, inhibition of progression or treatment of a diseasesassociated with excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose such as diabeticcomplications and diabetes, by inhibiting uptake, in particular,absorption in the small intestine, sugar reabsorption in the kidney,uptake into a cell and the like, of carbohydrates, glucose, fructose andmannose, and the like.

Specifically, the present invention relates to

[1] a pyrazole derivative represented by the following general formula(Iα):

wherein

R¹ represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (A), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (A), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B);

one of Q⁰ and T⁰ represents a group selected from

, and the other represents a group represented by the formula:—(CH₂)_(n)—Ar wherein Ar represents a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B) or a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(B); and n represents an integral number from 0 to 2, a C₁₋₆ alkokygroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (A), an optionally mono or di(C₁₋₆alkyl)-substituted amino group wherein the C₁₋₆ alkyl group may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), a C₂₋₉ heterocycloalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A), or a heterocycle-fused phenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B);

R represents a C₃₋₈ cycloalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A), a C₆₋₁₀ aryl group which may have the same or different 1 to 3groups selected from the following substituent group (B), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (B);

[Substituent Group (A)]:

a halogen atom, a nitro group, a cyano group, an oxo group, -G¹, —OG²,—SG², —N(G²)₂, —C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G²,S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂, —NHC(═O)G²,—OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹;

[Substituent Group (B)]:

a halogen atom, a nitro group, a cyano group, -G¹, —OG², —SG², —N(G²)₂,-G³OG⁴, -G³N(G⁴)₂, —C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G²,—S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂,—NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹;

in the above substituent group (A) and/or (B),

G¹ represents a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), a C₂₋₆alkenyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₂₋₆ alkynyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C), a C₃₋₈ cycloalkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D), a C₂₋₉ heterocycloalkyl group which may have the same or different1 to 3 groups selected from the following substituent group (C), or aC₁₋₉ heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (D);

G² represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D), and with the proviso that G² may be the same or different whenthere are 2 or more G² in the substituents;

G³ represents a C₁₋₆ alkyl group;

G⁴ represents a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), and withthe proviso that G⁴ may be the same or different when there are 2 ormore G⁴ in the substituents;

[Substituent Group (C)]:

a halogen atom, a nitro group, a cyano group, an oxo group, -G⁵, —OG⁶,—SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶,—S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶,—OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; and

[Substituent Group (D)]:

a halogen atom, a nitro group, a cyano group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂,—C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂,—S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵and —C(═O)NHS(═O)₂G⁵; in the substituent group (C) and/or (D),

G⁵ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl,a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkylgroup or a C₁₋₉ heteroaryl group; and

G⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉heterocycloalkyl group or a C₁₋₉ heteroaryl group, and with the provisothat G⁶ may be the same or different when there are 2 or more G⁶ in thesubstituents, or a pharmaceutically acceptable salt thereof or a prodrugthereof;

[2] a pyrazole derivative described in the above [1], wherein R¹represents a hydrogen atom, a C₁₋₆ alkyl group which may have the sameor different 1 to 3 groups selected from the substituent group (A), aC₃₋₈ cycloalkyl group which may have the same or different 1 to 3 groupsselected from the substituent group (A), or a C₆₋₁₀ aryl group which mayhave the same or different 1 to 3 groups selected from the substituentgroup (B); Q⁰ represents a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the substituent group (B); T⁰represents a group:

; R represents a C₆₋₁₀ aryl group which may have the same or different 1to 3 groups selected from the substituent group (B); substituent group(A) consists of a halogen atom, —OG², —SG², —N(G²)₂, —C(═O)OG²,—C(═O)N(G²)₂, —S(═O)₂OG² and —S(═O)₂N(G²)₂ in which G² represents ahydrogen atom, a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the substituent group (C); or a C₆₋₁₀ arylgroup which may have the same or different 1 to 3 groups selected fromthe substituent group (D); and substituent group (B) consists of ahalogen atom, a nitro group, a cyano group, -G¹, —OG², —SG², —C(═O)OG²in which G¹ represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the substituent group (C) or aC₆₋₁₀ aryl group which may have the same or different 1 to 3 groupsselected from the substituent group (D); and G² has the same meaning asdefined above, or a pharmaceutically acceptable salt thereof or aprodrug thereof;

[3] a pyrazole derivative described in the above [1], wherein one of Q⁰and T⁰ represents a group selected from

, and the other represents a group represented by the formula:—(CH₂)_(n)—Ar, or a pharmaceutically acceptable salt thereof or aprodrug thereof;

[4] a pyrazole derivative described in the above [3], wherein wherein Q⁰represents a C₆₋₁₀ aryl group which may have the same or different 1 to3 groups selected from the substituent group (B); T⁰ represents a groupselected from

, and R represents a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the substituent group (B), or apharmaceutically acceptable salt thereof or a prodrug thereof;

[5] a pyrazole derivative described in the above [4], wherein T⁰represents a group:

; and substituent group (B) consists of a halogen atom, a nitro group, acyano group, -G¹, —OG², —SG² and —C(═O)OG² in which G represents a C₁₋₆alkyl group which may have the same or different 1 to 3 groups selectedfrom the substituent group (C) or a C₆₋₁₀ aryl group which may have thesame or different 1 to 3 groups selected from the substituent group (D);and G² represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the substituent group (C)or a C₆₋₁₀ aryl group which may have the same or different 1 to 3 groupsselected from the substituent group (D), or a pharmaceuticallyacceptable salt thereof or a prodrug thereof;

[6] a pyrazole derivative described in the above [1], wherein one of Q⁰and T⁰ represents a group selected from

, and the other represents a C₁₋₆ alkoxy group which may have the sameor different 1 to 3 groups selected from the substituent group (A), anoptionally mono or di(C₁₋₆ alkyl)-substituted amino group in which theC₁₋₆ alkyl group may have the same or different 1 to 3 groups selectedfrom the substituent group (A), or a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from thesubstituent group (A), or a pharmaceutically acceptable salt thereof ora prodrug thereof;

[7] a pyrazole derivative described in the above [6], wherein Q⁰represents an optionally mono or di(C₁₋₆ alkyl)-substituted amino groupin which the C₁₋₆ alkyl group may have the same or different 1 to 3groups selected from the substituent group (A), or a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the substituent group (A); and T⁰ represents agroup selected from

, or a pharmaceutically acceptable salt thereof or a prodrug thereof;

[8] a pyrazole derivative described in the above [1], wherein one of Q⁰and T⁰ represents a group selected from

, and the other represents a heterocycle-fused phenyl group which mayhave the same or different 1 to 3 groups selected from the substituentgroup (B), or a pharmaceutically acceptable salt thereof or a prodrugthereof;

[9] a pyrazole derivative described in the above [8], wherein Q⁰represents a heterocycle-fused phenyl group which may have the same ordifferent 1 to 3 groups selected from the substituent group (B); and T⁰represents a group selected from

, or a pharmaceutically acceptable salt thereof or a prodrug thereof;

[10] a pharmaceutical composition comprising as an active ingredient apyrazole derivative described in any one of the above [1]-[9], or apharmaceutically acceptable salt thereof or a prodrug thereof;

[11] an inhibitor of 1,5-anhydroglucitol/fructose/mannose transportercomprising as an active ingredient a pyrazole derivative represented bythe following general formula (I):

wherein

R¹ represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (A), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (A), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B);

one of Q and T represents a group selected from

, and the other represents a group represented by the formula:—(CH₂)_(n)—Ar wherein Ar represents a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B) or a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(B); and n represents an integral number from 0 to 2, a C₁₋₆ alkyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (A), a C₁₋₆ alkoxy group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), an optionally mono or di(C₁₋₆ alkyl)-substituted amino groupwherein the C₁₋₆ alkyl group may have the same or different 1 to 3groups selected from the following substituent group (A), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the following substituent group (B);[Substituent Group (A)]:

a halogen atom, a nitro group, a cyano group, an oxo group, -G¹, —OG²,—SG², —N(G²)₂, —C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G², —S(═O)₂OG²,—S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂, —NHC(═O)G²,—OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹;

[Substituent Group (B)]:

a halogen atom, a nitro group, a cyano group, -G¹, —OG², —SG², —N(G²)₂,—G³OG⁴, —G³N(G⁴)₂, —C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G²,—S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂,—NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹;

in the above substituent group (A) and/or (B),

G¹ represents a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), a C₂₋₆alkenyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₂₋₆ alkynyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C), a C₃₋₈ cycloalkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D), a C₂₋₉ heterocycloalkyl group which may have the same or different1 to 3 groups selected from the following substituent group (C), or aC₁₋₉ heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (D);

G² represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D), and with the proviso that G² may be the same or different whenthere are 2 or more G² in the substituents;

G³ represents a C₁₋₆ alkyl group;

G⁴ represents a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), and withthe proviso that G⁴ may be the same or different when there are 2 ormore G⁴ in the substituents;

[Substituent Group (C)):

a halogen atom, a nitro group, a cyano group, an oxo group, -G⁵, —OG⁶,—SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG , -C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶,—S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶,—OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; and

[Substituent Group (D)]:

a halogen atom, a nitro group, a cyano group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂,—C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂,—S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵and —C(═O)NHS(═O)₂G⁵; in the substituent group (C) and/or (D),

G⁵ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl,a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkylgroup or a C₁₋₉ heteroaryl group; and

G⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉heterocycloalkyl group or a C₁₋₉ heteroaryl group, and with the provisothat G⁶ may be the same or different when there are 2 or more G⁶ in thesubstituents, or a pharmaceutically acceptable salt thereof or a prodrugthereof;

[12] an inhibitor of 1,5-anhydroglucitol/fructose/mannose transportercomprising as an active ingredient a pyrazole derivative described inany one of the above [1]-[9], or a pharmaceutically acceptable saltthereof or a prodrug thereof;

[13] an agent described in the above [11], which is an agent for theprevention, inhibition of progression or treatment of a diseaseassociated with the excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose;

[14] an agent for the prevention, inhibition of progression or treatmentof a disease associated with the excess uptake of at least a kind ofcarbohydrates selected from glucose, fructose and mannose comprising asan active ingredient a pyrazole derivative described in any one of theabove [1]-[9], or a pharmaceutically acceptable salt thereof or aprodrug thereof;

[15] an agent described in the above [13], wherein the diseaseassociated with the excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose is diabetic complications;

[16] an agent described in the above [14], wherein the diseaseassociated with the excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose is diabetic complications;

[17] an agent described in the above [15], wherein the diabeticcomplications is diabetic nephropathy;

[18] an agent described in the above [16], wherein the diabeticcomplications is diabetic nephropathy;

[19] an agent described in the above [13], wherein the diseaseassociated with the excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose is diabetes;

[20] an agent described in the above [14], wherein the diseaseassociated with the excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose is diabetes;

[21] a pharmaceutical combination which comprises (component a) apyrazole derivative described in any one of the above [1]-[9], or apharmaceutically acceptable salt thereof or a prodrug thereof, and(component b) at least one member selected from the group consisting ofan insulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulinor insulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationend products formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethylglutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and aurinaryalkalinizer;

[22] a pyrazole derivative represented by the following general formula(IIα):

wherein

R^(1A) represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A1), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (A1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (A1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B1);

one of Q^(A0) and T^(A0) represents a group selected from

having protective group(s), and the other represents a group representedby the formula: —(CH₂)_(n)—Ar wherein Ar^(A) represents a C₆₋₁₀ arylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (B1) or a C₁₋₉ heteroaryl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (B1); and n represents an integral number from 0 to 2,a C₁₋₆ alkoxy group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), an optionally monoor di(C₁₋₆ alkyl)-substituted amino group wherein the C₁₋₆ alkyl groupmay have the same or different 1 to 3 groups selected from the followingsubstituent group (A1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A1), or a heterocycle-fused phenyl group which may have the sameor different 1 to 3 groups selected from the following substituent group(B1);

R^(A) represents a C₃₋₈ cycloalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A1), a C₆₋₁₀ aryl group which may have the same or different 1 to 3groups selected from the following substituent group (B1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (B1);

[Substituent Group (A1)]:

a halogen atom, a nitro group, a cyano group, an oxo group, -G^(1A),—OG^(2B), —SG^(2B), —N(G^(2B))₂, —C(═O)G^(2A), —C(═O)OG^(2B),—C(═O)N(G^(2B))₂, —S(═O)₂G^(2A), —S(═O)₂OG^(2A), —S(═O)₂N(G^(2B))₂,—S(═O)G^(1A), —OC(═O)G^(1A), —OC(═O)N(G^(2B))₂, —NHC(═O)G^(2A),—OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and —C(═O)NHS(═O)₂G^(1A);

[Substituent Group (B1)]:

a halogen atom, a nitro group, a cyano group, -G^(1A), —OG^(2B),—SG^(2B), —N(G^(2B))₂, —G³OG^(4A), —G³N(G^(4A))₂, —C(═O)G^(2A),—C(═O)OG^(2B), —C(═O)N(G^(2B))₂, —S(═O)₂G^(2A), —S(═O)₂OG^(2A),—S(═O)₂N(G^(2B))₂, —S(═O)G^(1A), —OC(═O)G^(1A), —OC(═O)N(G^(2B))₂,—NHC(═O)G^(2A), —OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and—C(═O)NHS(═O)₂G^(1A);

in the above substituent group (A1) and/or (B1),

G^(1A) represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₂₋₆ alkenyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D1), a C₂₋₉heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D1);

G^(2A) represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (C1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D1);

G^(2B) represents a protective group, a hydrogen atom, a C₁₋₆ alkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₂₋₆ alkenyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C1), a C₂₋₆ alkynyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₃₋₈ cycloalkyl group which may have the same or different 1 to3 groups selected from the following substituent group (C1), a C₆₋₁₀aryl group which may have the same or different 1 to 3 groups selectedfrom the following substituent group (D1), a C₂₋₉ heterocycloalkyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C1), or a C₁₋₉ heteroaryl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (D1), and with the proviso that G^(2B) may be the sameor different when there are 2 or more G^(2B) in the substituents;

G³ represents a C₁₋₆ alkyl group;

G^(4A) represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), and with the proviso that G^(4A) may be the same or different whenthere are 2 or more G^(4A) in the substituents;

[Substituent Group (C1)]:

a halogen atom, a nitro group, a cyano group, -G⁵, —OG^(6A), —SG^(6A),—N(G^(6A))₂, —C(═O)G^(6A), —C(═O)OG^(6A), —C(═O)N(G^(6A))₂, —S(═O)₂G⁶,—S(O)₂OG⁶, —S(═O)₂N(G^(6A))₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G^(6A))₂,—NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; and

[Substituent Group (D1)]:

a halogen atom, a nitro group, a cyano group, -G⁵, —OG^(6A), —SG^(6A),—N(G^(6A))₂, —C(═O)G⁶, —C(═O)OG^(6A), —C(═O)N(G^(6A))₂, —S(═O)₂G⁶,—S(═O)₂OG⁶, —S(═O)₂N(G^(6A))₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G^(6A))₂,—NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; in thesubstituent group (C1) and/or (D1),

G⁵ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl,a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkylgroup or a C₁₋₉ heteroaryl group;

G⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉heterocycloalkyl group or a C₁₋₉ heteroaryl group; and

G^(6A) represents a protective group, a hydrogen atom, a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, aC₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroarylgroup, and with the proviso that G^(6A) may be the same or differentwhen there are 2 or more G^(6A) in the substituents, or apharmaceutically acceptable salt thereof;

[23] a pyrazole derivative represented by the following general formula(IIIα):

wherein

R^(1A) represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A1), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (A1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (A1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B1);

one of Q^(B0) and T^(B0) represents a hydroxy group, and the otherrepresents a group represented by the formula: —(CH₂)_(n)—Ar^(A) whereinAr^(A) represents a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B1) or a C₁₋₉ heteroaryl group which may have the same or different 1to 3 groups selected from the following substituent group (B1); and nrepresents an integral number from 0 to 2, a C₁₋₆ alkoxy group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A1), an optionally mono or di(C₁₋₆ alkyl)-substitutedamino group wherein the C₁₋₆ alkyl group may have the same or different1 to 3 groups selected from the following substituent group (A1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the following substituent group (B1);

R^(A) represents a C₃₋₈ cycloalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A1), a C₆₋₁₀ aryl group which may have the same or different 1 to 3groups selected from the following substituent group (B1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (B1);

[Substituent Group (A1)]:

a halogen atom, a nitro group, a cyano group, an oxo group, -G^(1A),—OG^(2B), —SG^(2B), —N(G^(2B))₂, —C(═O)G^(2A), —C(═O)OG^(2B),—C(═O)N(G^(2B))₂, —S(═O)₂G^(2A), —S(═O)₂OG^(2A), —S(═O)₂N(G^(2B))₂,—S(═O)G^(1A), —OC(═O)G^(1A), —OC(═O)N(G^(2B))₂, —NHC(═O)G^(2A),—OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and —C(═O)NHS(═O)₂G^(1A);

[Substituent Group (B1)]:

a halogen atom, a nitro group, a cyano group, -G^(1A), —OG^(2B),—SG^(2B), —N(G^(2B))₂, —G³OG^(4A), —G³N(G^(4A))₂, —C(═O)G^(2A),—C(═O)OG^(2B), —C(═O)N(G^(2B))₂, —S(═O)₂G^(2A), —S(═O)₂OG^(2A),—S(═O)₂N(G^(2B))₂, —S(═O)G^(1A), —OC(═O)G^(1A), —OC(═O)N(G^(2B))₂,—NHC(═O)G^(2A), —OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and—C(═O)NHS(═O)₂G^(1A);

in the above substituent group (A1) and/or (B1),

G^(1A) represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₂₋₆ alkenyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D1);

G^(2A) represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (C1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D1);

G^(2B) represents a protective group, a hydrogen atom, a C₁₋₆ alkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₂₋₆ alkenyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C1), a C₂₋₆ alkynyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₃₋₈ cycloalkyl group which may have the same or different 1 to3 groups selected from the following substituent group (C1), a C₆₋₁₀aryl group which may have the same or different 1 to 3 groups selectedfrom the following substituent group (D1), a C₂₋₉ heterocycloalkyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C1), or a C₁₋₉ heteroaryl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (D1), and with the proviso that G^(2B) may be the sameor different when there are 2 or more G^(2B) in the substituents;

G³ represents a C₁₋₆ alkyl group;

G^(4A) represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), and with the proviso that G^(4A) may be the same or different whenthere are 2 or more G^(4A) in the substituents;

[Substituent Group (C1)]:

a halogen atom, a nitro group, a cyano group, an oxo group, -G⁵,—OG^(6A), —SG^(6A), —N(G^(6A))₂, —C(═O)G⁶, —C(═O)OG^(6A),—C(═O)N(G^(6A))₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G^(6A))₂, —S(═O)G⁵,—OC(═O)G⁵, —OC(═O)N(G^(6A))₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and—C(═O)NHS(═O)₂G⁵; and

[Substituent Group (D1)]:

a halogen atom, a nitro group, a cyano group, -G⁵, —OG^(6A), —SG^(6A),—N(G^(6A))₂, —C(═O)G⁶, —C(═O)OG^(6A), —C(═O)N(G^(6A))₂, —S(═O)₂G⁶,—S(═O)₂OG⁶, —S(═O)₂N(G^(6A))₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G^(6A))₂,—NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵;

in the substituent group (C1) and/or (D1),

G⁵ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl,a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkylgroup or a C₁₋₉ heteroaryl group;

G⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉heterocycloalkyl group or a C₁₋₉ heteroaryl group; and

G^(6A) represents a protective group, a hydrogen atom, a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, aC₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroarylgroup, and with the proviso that G^(6A) may be the same or differentwhen there are 2 or more G^(6A) in the substituents, or apharmaceutically acceptable salt thereof; and the like.

In the present invention, the term “C₁₋₆ alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “C₂₋₆ alkenyl group” means astraight-chained or branched alkenyl group having 2 to 6 carbon atomssuch as a vinyl group, an allyl group, a 1-propenyl group, anisopropenyl group, a 1-butenyl group, a 2-butenyl group, a 2-methylallylgroup or the like; the term “C₂₋₆ alkynyl group” means astraight-chained or branched alkynyl group having 2 to 6 carbon atomssuch as an ethynyl group, a 2-propynyl group or the like; the term “C₁₋₆alkoxy group” means a straight-chained or branched alkoxy group having 1to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxygroup, an isopropoxy group, a butoxy group, an isobutoxy group, asec-butoxy group, a tert-butoxy group, a pentyloxy group, anisopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, ahexyloxy group or the like; the term “optionally mono or di(C₁₋₆alkyl)-substituted amino group” means an amino group optionallymono-substituted by the above C₁₋₆ alkyl group or di-substituted by thesame or different C₁₋₆ alkyl groups as defined above; the term “C₃₋₈cycloalkyl group” means a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a cyclohexyl group, a cycloheptyl group or acyclooctyl group; the term “C₆₋₁₀ aryl group” means a phenyl group or anaphthyl group; the term “C₂₋₉ heterocycloalkyl group” means a 3 to8-membered heterocycloalkyl group containing the same or different 1 or2 hetero atoms other than the binding position selected from an oxygenatom, a sulfur atom and a nitrogen atom in the ring, which is derivedfrom morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran,aziridine, azetidine, pyrrolidine, imidazolidine, oxazoline, piperidine,piperazine, pyrazolidine or the like, or a 5 or 6-memberedheterocycloalkyl group as defined above fused with an aliphatic oraromatic carbocycle or heterocycle such as a cyclohexane ring, a benzenering, a pyridine ring or the like; the term “C₁₋₉ heteroaryl group”means a 5 or 6-membered heteroaryl group containing the same ordifferent 1 to 4 hetero atoms other than the binding position selectedfrom an oxygen atom, a sulfur atom and a nitrogen atom in the ring,which is derived from thiazole, oxazole, isothiazole, isoxazole,pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, thiophene,imidazole, pyrazole, oxadiazole, thiodiazole, tetrazole, furazan or thelike, or the above heteroaryl group fused with a 5 or 6-memberedaromatic carbocycle or heterocycle such as a benzene ring, a pyrazolering, a pyridine ring or the like; the term “heterocycle-fused phenylgroup” means a phenyl group fused with a 3 to 8-memberedheterocycloalkene containing the same or different 1 or 2 hetero atomsselected from an oxygen atom, a sulfur atom and a nitrogen atom in thering, which is derived from dioxane, dioxolan, morpholine,thiomorpholine, tetrahydrofuran, tetrahydropyran, azetidine,pyrrolidine, imidazolidine, oxazolidine, piperidine, piperazine,pyrazolidine or the like, or a phenyl group fused with a 5 or 6-memberedaromatic heterocycle containing the same or different 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom inthe ring such as thiazole, oxazole, isothiazole, isoxazole, pyridine,pyrimidine, pyrazine, pyridazine, pyrrole, thiophene, imidazole,pyrazole or the like; the term “halogen atom” means a fluorine atom, achlorine atom, a bromine atom or an iodine atom; the term“hydroxy-protective group” means a hydroxy-protective group used ingeneral organic syntheses such as a benzyl group, a p-methoxybenzylgroup, a p-nitrobenzyl group, a methoxymethyl group, an acetyl group, atert-butyldimethylsilyl group, a triisopropylsilyl group, an allylgroup, a benzoyl group, a pivaloyl group, a benzyloxycarbonyl group orthe like; the term “thiol-protective group” means a thiol-protectivegroup used in general organic syntheses such as a benzyl group, ap-methoxybenzyl group, a p-nitrobenzyl group, a triphenylmethyl group, amethoxymethyl group, an acetyl group, a benzoyl group, a pivaloyl group,a benzyloxycarbonyl group, an ethylaminocarbonyl group or the like; theterm “amino-protective group” means an amino-protective group used ingeneral organic syntheses such as a benzyloxycarbonyl group, atert-butoxy-carbonyl group, a benzyl group, a trifluoroacetyl group orthe like; the term “carboxy-protective group” means a carboxy-protectivegroup used in general organic syntheses such as a benzyl group, atert-butyldimethylsilyl group, an allyl group, a methyl group, an ethylgroup or the like; and the term “amide-protective group” means anamide-protective group used in general organic syntheses such as a tosylgroup, a methoxymethyl group, a benzyloxymethyl group, an allyl group, atriusopropylsilyl group, a benzyl group, a methoxycarbonyl group or thelike.

For example, the compounds represented by the above general formula (I)of the present invention can be prepared according to the followingprocedure:

wherein

G represents a group selected from a β-D-glucopyranosyloxy group, aβ-D-mannopyranosyloxy group, an α-D-glucopyranosyloxy, anα-D-mannopyranosyloxy group, β-D-2-deoxyglucopyranosyloxy group and anα-D-2-deoxyglucopyranosyloxy group, which has a hydroxy-protective groupat a hydroxy group;

X represents a leaving group such as a bromine atom;

X¹ represents a leaving group such as a halogen atom, a mesyloxy group,a tosyloxy group;

R^(1B) represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the above substituent group (A1),a C₂₋₆ alkenyl group which may have the same or different 1 to 3 groupsselected from the above substituent group (A1), a C₂₋₆ alkynyl groupwhich may have the same or different 1 to 3 groups selected from theabove substituent group (A1), a C₃₋₈ cycloalkyl group which may have thesame or different 1 to 3 groups selected from the above substituentgroup (A1), a C₆₋₁₀ aryl group which may have the same or different 1 to3 groups selected from the above substituent group (B1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the above substituent group (A1), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the above substituent group (B1);

one of Q^(A) and T^(A) represents a group selected from

, and the other represents a group represented by the formula:—(CH₂)_(n)—Ar^(A) wherein Ar^(A) represented a C₆₋₁₀ aryl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (B1) or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (B1); and n represents an integral number from 0 to 2, a C₁₋₆alkyl group which may have the same or different 1 to 3 groups selectedfrom the following substituent group (A1), a C₁₋₆ alkoxy group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A1), an optionally mono or di(C₁₋₆ alkyl)-substitutedamino group wherein the C₁₋₆ alkyl group may have the same or different1 to 3 groups selected from the following substituent group (A1), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the following substituent group (B1);

one of Q^(B) and T^(B) represents a hydroxy group, and the otherrepresents a group represented by the formula: —(CH₂)_(n)—Ar^(A) whereinAr^(A) represented a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B1) or a C₁₋₉ heteroaryl group which may have the same or different 1to 3 groups selected from the following substituent group (B1); and nrepresents an integral number from 0 to 2, a C₁₋₆ alkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A1), a C₁₋₆ alkoxy group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A1), an optionally mono or di(C₁₋₆ alkyl)-substituted amino groupwherein the C₁₋₆ alkyl group may have the same or different 1 to 3groups selected from the following substituent group (A1), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the following substituent group (B1);

and R, R¹, R^(1A), R^(A), Q and T have the same meanings as definedabove.

Process 1

A compound represented by the above general formula (II) can be preparedby subjecting a pyrazole derivative represented by the above generalformula (III) to glycosidation using a sugar donor represented by theabove general formula (IV) 1) in the presence of a base such as sodiumhydroxide, potassium hydroxide, potassium carbonate or the like and aphase transfer catalyst such as benzyltri(n-butyl)ammonium chloride,benzyltri-(n-butyl)ammonium bromide, tetra(n-butyl)ammonium hydrogensulfate or the like in water and an inert solvent, 2) in the presence ofsilver carbonate in tetrahydrofuran, or 3) in the presence of potassiumcarbonate in acetonitrile or tetrahydrofuran, and optionally toN-alkylation using an alkylating agent represented by the above generalformula (V) in the presence of a base such as cesium carbonate,potassium carbonate or sodium hydride and optionally in the presence ofa catalytic amount of sodium iodide in an inert solvent. As the inertsolvent used in the glycosidation, for example, dichloromethane,toluene, benzotrifluoride and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature. As the solventused in the N-alkylation, for example, acetonitrile, ethanol,1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. The obtainedcompound represented by the above general formula (II) can be also usedin the process 2 after converting into a salt thereof in the usual way.

Process 2

A compound represented by the above general formula (I) of the presentinvention can be prepared by subjecting a compound represented by theabove general formula (II), after removing the protective group of sugarmoiety or the like in accordance with a method used in general organicsyntheses such as alkaline hydrolysis, optionally to N-Alkylation usingan alkylating agent represented by the above general formula (V) in thepresence of a base such as cesium carbonate, potassium carbonate orsodium hydride and optionally in the presence of a catalytic amount ofsodium iodide in an inert solvent, and in a case that there is aprotective group other than the sugar moiety, by removing the protectivegroup in accordance with a method used in general organic synthesis. Asthe inert solvent used in the hydrolysis reaction, methanol, ethanol,tetrahydrofuran, water, a mixed solvent thereof and the like can beillustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide, methylamine, dimethylamine and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. As the solvent used in the N-alkylation, for example,acetonitrile, ethanol, 1,2-dimethoxyethane, tetrahydrofuran,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,dimethyl sulfoxide, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 10 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

Of the compounds represented by the above general formula (I) of theinvention, a compound having a C₁₋₆ alkoxy group which may have varioussubstituents, for example, can be prepared by subjecting a correspondinghydroxy compound to O-alkylation using an O-alkylating agent such as acorresponding C₁₋₆ alkyl halide in the presence of a base such as cesiumcarbonate, potassium carbonate or sodium hydride and optionally in thepresence of a catalytic amount of sodium iodide in an inert solvent. Asthe inert solvent used in the O-alkylation, for example, acetonitrile,ethanol, 1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. In the aboveprocesses 1 to 2, the above O-alkylation can be subjected to acorresponding hydroxy derivative suitably derived as a productionintermediate, and the resulting compound can be treated in a similarmanner to produce a compound of the present invention.

Of the compounds represented by the above general formula (I) of theinvention, a compound wherein one of Q and T represents aβ-D-mannopyranosyloxy group, for example, can be also prepared accordingto the following procedures:

wherein one of Q^(C) and T^(C) represents a group of the formula:

having a protective group, and the other represents a group representedby the formula: —(CH₂)_(n)—Ar^(A) in which Ar^(A) and n have the samemeanings as defined above, a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the above substituent group (A1),a C₁₋₆ alkoxy group which may have the same or different 1 to 3 groupsselected from the above substituent group (A1), an optionally mono ordi(C₁₋₆ alkyl)-substituted amino group wherein the C₁₋₆ alkyl group mayhave the same or different 1 to 3 groups selected from the abovesubstituent group (A1), a C₃₋₈ cycloalkyl group which may have the sameor different 1 to 3 groups selected from the above substituent group(A1), a C₂₋₉ heterocycloalkyl group which may have the same or different1 to 3 groups selected from the above substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the above substituent group (B1);

one of Q^(D) and T^(D) represents a β-D-mannopyranosyloxy group having aprotective group, and the other represents a group represented by theformula: —(CH₂)_(n)—Ar^(A) in which Ar^(A) and n have the same meaningsas defined above, a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the above substituent group (A1),a C₁₋₆ alkoxy group which may have the same or different 1 to 3 groupsselected from the above substituent group (A1), an optionally mono ordi(C₁₋₆ alkyl)-substituted amino group wherein the C₁₋₆ alkyl group mayhave the same or different 1 to 3 groups selected from the abovesubstituent group (A1), a C₃₋₈ cycloalkyl group which may have the sameor different 1 to 3 groups selected from the above substituent group(A1), a C₂₋₉heterocycloalkyl group which may have the same or different1 to 3 groups selected from the above substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the above substituent group (B1);

one of Q^(1a) and T^(1a) represents a β-D-mannopyranosyloxy group, andthe other represents a group represented by the formula:—(CH₂)_(n)—Ar^(A) in which Ar^(A) and n have the same meanings asdefined above, a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the above substituent group (A1), a C₁₋₆alkoxy group which may have the same or different 1 to 3 groups selectedfrom the above substituent group (A1), an optionally mono or di(C₁₋₆alkyl)-substituted amino group wherein the C₁₋₆ alkyl group may have thesame or different 1 to 3 groups selected from the above substituentgroup (A1), a C₃₋₈ cycloalkyl group which may have the same or different1 to 3 groups selected from the above substituent group (A1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the above substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the above substituent group (B1); and

R, R¹, R^(1A), R^(1B), R^(A), Q^(B), T^(B), X and X¹ have the samemeanings as defined above.

Process 3

A compound represented by the above general formula (VII) can beprepared by subjecting a pyrazole derivative represented by the abovegeneral formula (III) to glycosidation using a sugar donor representedby the above general formula (VI) in the presence of a base such assilver carbonate in an inert solvent. As the inert solvent used in theglycosidation, for example, dichloromethane, toluene, tetrahydrofuranand the like can be illustrated. The reaction temperature is usuallyfrom 0° C. to reflux temperature, and the reaction time is usually from30 minutes to 1 day, varying based on a used starting material, solventand reaction temperature.

Process 4

A corresponding compound represented by the above general formula (IIa)can be prepared by subjecting a compound represented by the abovegeneral formula (VII) to reduction using a reducing agent such as sodiumborohydride, diisobutylaluminum hydride, triisopropoxyalminum hydride orthe like in an inert solvent, and optionally to N-alkylation using analkylating agent represented by the above general formula (V) in thepresence of a base such as cesium carbonate, potassium carbonate orsodium hydride and optionally in the presence of a catalytic amount ofsodium iodide in an inert solvent. As the inert solvent used in thereduction, for example, methanol, ethanol, tetrahydrofuran, diethylether, toluene, a mixed solvent thereof and the like can be illustrated.The reaction temperature is usually from −78° C. to reflux temperature,and the reaction time is usually from 30 minutes to 1 day, varying basedon a used starting material, solvent and reaction temperature. As thesolvent used in the N-alkylation, for example, acetonitrile, ethanol,1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. The obtainedcompound represented by the above general formula (IIa) can be also usedin the process 5 after converting into a salt thereof in the usual way.

Process 5

A compound represented by the above general formula (Ia) of the presentinvention can be prepared by subjecting a compound represented by theabove general formula (IIa), after removing the protective group ofsugar moiety or the like in accordance with a method used in generalorganic syntheses such as alkaline hydrolysis, optionally toN-Alkylation using an alkylating agent represented by the above generalformula (V) in the presence of a base such as cesium carbonate,potassium carbonate or sodium hydride and optionally in the presence ofa catalytic amount of sodium iodide in an inert solvent, and in a casethat there is a protective group other than the sugar moiety, byremoving the protective group in accordance with a method used ingeneral organic syntheses. As the inert solvent used in the hydrolysisreaction, for example, methanol, ethanol, tetrahydrofuran, water, amixed solvent thereof and the like can be illustrated. As the base, forexample, sodium hydroxide, sodium methoxide, sodium ethoxide,methylamine, dimethylamine and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature. As the solventused in the N-alkylation, for example, acetonitrile, ethanol,1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

A compound represented by the above general formula (III) of the presentinvention used as a starting material in the above production processes,for example, can be prepared according to the following procedures:

wherein Y represents a leaving group such as a halogen atom, a mesyloxygroup, a tosyloxy group; L represents MgBr, MgCl, MgI, ZnI, ZnBr, ZnClor a lithium atom; R¹² represents a group represented by the formula:—(CH₂)_(n)—Ar^(A) in which Ar^(A) and n have the same meanings asdefined above, a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the above substituent group (A1), a C₁₋₆alkoxy group which may have the same or different 1 to 3 groups selectedfrom the above substituent group (A1), an optionally mono or di(C₁₋₆alkyl)-substituted amino group wherein the C₁₋₆ alkyl group may have thesame or different 1 to 3 groups selected from the above substituentgroup (A1), a C₃₋₈ cycloalkyl group which may have the same or different1 to 3 groups selected from the above substituent group (A1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the above substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the above substituent group (B1); R⁰ represents aC₁₋₆ alkyl group; PG represents a hydroxy-protective group; one of Q^(E)and T^(E) represents a group represented by the formula: —O—PG, and theother represents R¹²; one of Q^(F) and T^(F) represents a grouprepresented by the formula: —O—PG, and the other represents a halogenatom; X² represents a halogen atom; and R^(1A), R^(A), Q^(B) and T^(B)have the same meanings as defined above.Process A

A compound represented by the above general formula (X) can be preparedby condensing a compound represented by the above general formula (VIII)with a ketoacetate ester compound represented by the above generalformula (IX) in the presence of a base such as sodium hydride, potassiumtert-butoxide or the like in an inert solvent. As the inert solvent usedin the condensing reaction, for example, 1,2-dimethoxyethane,tetrahydrofuran, N,N-dimethylformamide, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from1 hour to 1 day, varying based on a used starting material, solvent andreaction temperature.

Process B

A pyrazole derivative represented by the above general formula (III) ofthe present invention can be prepared by condensing a compoundrepresented by the above general formula (X) with a hydrazine compoundrepresented by the above general formula (XI) or a hydrate thereof or asalt thereof in the presence or absence of a base in an inert solvent,and introducing a protective group in the usual way as occasion demands.As the inert solvent used in the condensing reaction, for example,toluene, tetrahydrofuran, chloroform, methanol, ethanol, a mixed solventthereof and the like can be illustrated, and ass the base, for example,triethylamine, diisopropylethylamine, pyridine, sodium methoxide, sodiumethoxide and the like can be illustrated. The reaction temperature isusually from room temperature to reflux temperature, and the reactiontime is usually from 1 hour to 1 day, varying based on a used startingmaterial, solvent and reaction temperature. The obtained pyrazolederivative represented by the above general formula (III) can be alsoused in the subsequent process after converting into a salt thereof inthe usual way.

Process C

A compound represented by the above general formula (XIV) can beprepared by condensing a dithiocarbonate ester compound represented bythe above general formula (XII) with a ketone compound represented bythe above general formula (XIII) in the presence of a base such assodium amide in an inert solvent. As the inert solvent used in thecondensing reaction, for example, toluene and the like can beillustrated. The reaction temperature is usually from −20° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process D

A pyrazole derivative represented by the above general formula (XV) canbe prepared by condensing a compound represented by the above generalformula (XIV) with a hydrazine compound represented by the above generalformula (XI) or a hydrate thereof or a salt thereof in the presence of abase such as triethylamine or diisopropylethylamine in an inert solvent,and introducing a protective group as occasion demands. As the inertsolvent used in the condensing reaction, for example, acetonitrile andthe like can be illustrated. The reaction temperature is usually from 0°C. to reflux temperature, and the reaction time is usually from 1 hourto 1 day, varying based on a used starting material, solvent andreaction temperature.

Process E

A pyrazole aldehyde derivative represented by the above general formula(XVI) can be prepared by subjecting a compound represented by the abovegeneral formula (XV) to folmylation by a reaction such as Vilsmeierreaction using phosphorus oxychloride and N,N-dimethylformamide. As thesolvent used in the folmylating reaction, for example,N,N-dimethylformamide and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process F

A compound represented by the above general formula (XVIII) can beprepared by condensing a compound represented by the above generalformula (XVI) with a Grignard reagent, a Reformatsky reagent or alithium reagent represented by the above general formula (XVII) in aninert solvent. As the inert solvent used in the condensing reaction, forexample, tetrahydrofuran, diethyl ether, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from −78°C. to room temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

Process G

A pyrazole derivative represented by the above general formula (III) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (XVIII) to catalytichydrogenation using a palladium catalyst such as palladium-carbon powderin the presence or absence of an acid such as hydrochloric acid in aninert solvent, and in a case that a compound represented by the abovegeneral formula (XVIII) has any sulfur atom, subjecting the resultingcompound to acid treatment in an aqueous solution of trifluoroaceticacid and dimethyl sulfide usually at 0° C. to reflux temperature for 30minutes to 1 day as occasion demands. As the inert solvent used in thecatalytic hydrogenation, for example, methanol, ethanol,tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. The obtainedpyrazole derivative represented by the above general formula (III) canbe also used in the subsequent process after suitably converting into asalt thereof in the usual way.

Process H

A brominated compound represented by the above general formula (XIX) canbe prepared by brominating a compound represented by the above generalformula (XV) using bromine in an inert solvent. As the inert solventused in the brominating reaction, dichloromethane, chloroform, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from −40° C. to room temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process I

A compound represented by the above general formula (XVIII) can beprepared by converting a compound represented by the above generalformula (XIX) into a lithium compound using n-butyllithium in the usualway or a Grignard reagent using magnesium in the usual way, andcondensing using a formyl derivative represented by the above generalformula (XX) in an inert solvent. As the inert solvent used in thecondensing reaction, for example, tetrahydrofuran, diethyl ether, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from −78° C. to room temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process J

A compound represented by the above general formula (XXII) can beprepared by condensing a compound represented by the above generalformula (XXI) with R¹²—B(OR³)₂ wherein R³ represents a hydrogen atom ora lower alkyl group or both R³ bind together to form a lower alkylenegroup; and R¹² has the same meaning as defined above, in the presence ofa palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) orpalladium(II) acetate and a base such as sodium carbonate, cesiumfluoride, potassium phosphate or sodium hydroxide and in the presence orabsence of a phase transfer catalyst such as tetrabutylammonium bromide.As the inert solvent used in the condensing reaction (Suzuki couplingreaction), for example, N,N-dimethylformamide, tetrahydrofuran,1,2-dimethoxyethane, water, toluene, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is from roomtemperature to reflux temperature.

Process K

A compound represented by the above general formula (XVIII) can beprepared by subjecting a compound represented by the above generalformula (XXII) to reduction using a reducing agent such as sodiumborohydride, diisobutylaluminum hydride or lithium aluminum hydride inan inert solvent. As the inert solvent used, for example, toluene,tetrahydrofuran, dichloromethane, methanol, a mixed solvent thereof andthe like can be illustrated. The reaction temperature is usually from−78° C. to reflux temperature, and the reaction time is usually from 30minutes to 1 day, varying based on a used starting material, solvent andreaction temperature.

Process L

A compound represented by the above general formula (III) of the presentinvention can be prepared by subjecting a compound represented by theabove general formula (XXII) to reduction using a reducing agent such astriethylsilyl halide in the presence of a Lewis acid such astrifluoroacetic acid or borontrifluoride diethyl ether complex withoutsolvent or in an inert solvent and then optionally removing thehydroxy-protective group in the usual way. As the inert solvent used inthe reducing reaction, for example, toluene, tetrahydrofuran,dichloromethane, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

Process M

A compound represented by the above general formula (XXIV) can beprepared by condensing a compound represented by the above generalformula (XXIII) with R¹²—B(OR³)₂ wherein R³ and R¹² have the samemeanings as defined above, in the presence of a palladium catalyst suchas tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate andabase such as sodium carbonate, cesium fluoride, potassium phosphate orsodium hydroxide and in the presence or absence of a phase transfercatalyst such as tetrabutylammonium bromide. As the inert solvent usedin the condensing reaction (Suzuki coupling reaction), for example,N,N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane, water,toluene, a mixed solvent thereof and the like can be illustrated. Thereaction temperature is from room temperature to reflux temperature.

Process N

A compound represented by the above general formula (XXV) can beprepared by subjecting a compound represented by the above generalformula (XXIV) to reduction using a reducing agent such as lithiumaluminum hydride or diisobutylaluminum hydride in an inert solvent. Asthe inert solvent used in the reduction, for example, toluene,tetrahydrofuran, dichloromethane, a mixed solvent thereof and the likecan be illustrated. The reaction temperature is usually from −78° C. toreflux temperature, and the reaction time is usually from 30 minutes to1 day, varying based on a used starting material, solvent and reactiontemperature.

Process O

A compound represented by the above general formula (XVI) can beprepared by subjecting a compound represented by the above generalformula (XXV) to oxidation using dimethylsulfoxide such as Swernoxidation, chromic acid oxidation using pyridinium chlorochromate,pyridinium dichromate or the like in an inert solvent or oxidation usingan oxygenating agent such as manganese dioxide. As the inert solventused in the oxidation, for example, toluene, tetrahydrofuran,dichloromethane, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from −78° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process P

A compound represented by the above general formula (XVI) can beprepared by subjecting a compound represented by the above generalformula (XXIV) to reduction using a reducing agent such astriisopropoxyalminum hydride or diisobutylaluminum hydride in an inertsolvent. As the inert solvent used in the reduction, for example,toluene, tetrahydrofuran, hexane, diethyl ether, dichloromethane, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from −78° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

A compound represented by the above general formula (XXII) used as astarting material in the above production processes, for example, can beprepared according to the following procedures:

wherein X³ represents a halogen atom such as a chlorine atom; and L, R⁰,R^(1A), R^(A), Q^(E) and T^(E) have the same meanings as defined above.Process Q

A compound represented by the above general formula (XXVII) can beprepared by treating a compound represented by the above general formula(XXVI) according to a method used in general organic syntheses such asalkaline hydrolysis. As the solvent used in the hydrolysis reaction, forexample, methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane,water, a mixed solvent thereof and the like can be illustrated. As thebase, for example, sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Process R

A compound represented by the above general formula (XXVIII) can beprepared by halogenating a compound represented by the above generalformula (XXVII) using an acid halogenating agent such as thionylchloride, phosphorus trichloride, phosphorus pentachloride, phosphorusoxychloride, phosphorus tribromide or fluorosulfuric acid withoutsolvent or in an inert solvent. As the inert solvent used in thehalogenation, for example, toluene, dichloromethane, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from −78° C. to reflux temperature, and the reaction time isusually from 30 minutes to 1 day, varying based on a used startingmaterial, solvent and reaction temperature.

Process S

A compound represented by the above general formula (XXII) can beprepared by condensing a compound represented by the above generalformula (XXVIII) with a Grignard reagent, a Reformatsky reagent or alithium reagent represented by the above general formula (XVII) in aninert solvent. As the inert solvent used in the condensing reaction, forexample, tetrahydrofuran, diethyl ether, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from −78°C. to room temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

A compound represented by the above general formula (XXI) used as astarting material in the above production processes, for example, can beprepared according to the following procedures:

wherein L, R⁰, R^(1A), R^(A), Q^(F), T^(F) and X³ have the same meaningsas defined above.Process T

A compound represented by the above general formula (XXX) can beprepared by subjecting a compound represented by the above generalformula (XXIX) to reduction using a reducing agent such astriisopropoxyalminum hydride or diisobutylaluminum hydride in an inertsolvent. As the inert solvent used in the reduction, for example,toluene, tetrahydrofuran, hexane, diethyl ether, dichloromethane, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from −78° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process U

A compound represented by the above general formula (XXXI) can beprepared by treating a compound represented by the above general formula(XXIX) according to a method used in general organic syntheses such asalkaline hydrolysis. As the solvent used in the hydrolysis reaction, forexample, methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane,water, a mixed solvent thereof and the like can be illustrated. As thebase, for example, sodium hydroxide, sodium methoxide, sodium ethoxide,potassium hydroxide and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Process V

A compound represented by the above general formula (XXXII) can beprepared by subjecting a compound represented by the above generalformula (XXXI) to reduction using a reducing agent such as lithiumaluminum hydride, borane-dimethylsulfide complex orborane-tetrahydrofuran complex in an inert solvent. As the inert solventused in the reduction, for example, toluene, tetrahydrofuran,dichloromethane, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from −78° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process W

A compound represented by the above general formula (XXXII) can beprepared by subjecting a compound represented by the above generalformula (XXIX) to reduction using a reducing agent such as lithiumaluminum hydride or diisobutylaluminum hydride in an inert solvent. Asthe inert solvent used in the reduction, for example, toluene,tetrahydrofuran, dichloromethane, a mixed solvent thereof and the likecan be illustrated. The reaction temperature is usually from −78° C. toreflux temperature, and the reaction time is usually from 30 minutes to1 day, varying based on a used starting material, solvent and reactiontemperature.

Process X

A compound represented by the above general formula (XXX) can beprepared by subjecting a compound represented by the above generalformula (XXXII) to oxidation using dimethylsulfoxide such as Swernoxidation, chromic acid oxidation using pyridinium chlorochromate,pyridinium dichromate or the like in an inert solvent or oxidation usingan oxygenating agent such as manganese dioxide. As the inert solventused in the above oxidation, for example, toluene, tetrahydrofuran,dichloromethane, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from −78° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process Y

A compound represented by the above general formula (XXXIII) can beprepared by condensing a compound represented by the above generalformula (XXX) with a Grignard reagent, a Reformatsky reagent or alithium reagent represented by the above general formula (XVII) in aninert solvent. As the solvent used in the condensing reaction, forexample, tetrahydrofuran, diethyl ether, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from −78°C. to room temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

Process Z

A compound represented by the above general formula (XXI) can beprepared by subjecting a compound represented by the above generalformula (XXXIII) to oxidation using dimethylsulfoxide such as Swernoxidation, chromic acid oxidation using pyridinium chlorochromate,pyridinium dichromate or the like in an inert solvent or oxidation usingan oxygenating agent such as manganese dioxide. As the inert solventused in the oxidation, for example, toluene, tetrahydrofuran,dichloromethane, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from −78° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process α

A compound represented by the above general formula (XXXIV) can beprepared by halogenating a compound represented by the above generalformula (XXXI) using an acid halogenating agent such as thionylchloride, phosphorus trichloride, phosphorus pentachloride, phosphorusoxychloride, phosphorus tribromide or fluorosulfuric acid withoutsolvent or in an inert solvent. As the inert solvent used in thehalogenation, for example, toluene, dichloromethane, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from −78° C. to reflux temperature, and the reaction time isusually from 30 minutes to 1 day, varying based on a used startingmaterial, solvent and reaction temperature.

Process β

A compound represented by the above general formula (XXI) can beprepared by condensing a compound represented by the above generalformula (XXXIV) with a Grignard reagent, a Reformatsky reagent or alithium reagent represented by the above general formula (XVII) in aninert solvent. As the inert solvent used in the condensing reaction, forexample, tetrahydrofuran, diethyl ether, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from −78°C. to room temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

A compound represented by the above general formula (XXIX) including acompound represented by the above general formula (XXIII) used as astarting material in the above production processes, for example, can beprepared according to the following procedures:

wherein one of Q^(G) and T^(G) represents a hydroxy group, and the otherrepresents a hydrogen atom; one of Q^(H) and T^(H) represents a hydroxygroup, and the other represents a halogen atom; one of Q^(I) and T^(I)represents a group represented by the formula: —O—PG, and the otherrepresents a hydrogen atom; and PG, R⁰, R^(1A), Q^(F) and T^(F) have thesame meanings as defined above.Process γ

A pyrazole derivative represented by the above general formula (XXXVI)can be prepared by condensing a compound represented by the abovegeneral formula (XXXV) with a hydrazine compound represented by theabove general formula (XI) or a hydrate thereof or a salt thereof in thepresence or absence of a base in an inert solvent. As the inert solventused in the condensing reaction, for example, toluene, tetrahydrofuran,dichloromethane, N,N-dimethylformamide, ethanol, water, a mixed solventthereof and the like can be illustrated. As the base, for example,sodium hydride, sodium amide, sodium carbonate, sodium ethoxide and thelike can be illustrated. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from10 minutes to 1 day, varying based on a used starting material, solventand reaction temperature.

Process δ

A compound represented by the above general formula (XXXVII) can beprepared by halogenating a compound represented by the above generalformula (XXXVI) using a halogenating agent such as sulfuryl chloride,N-chlorosuccinimide or N-bromosuccinimide in an inert solvent. As theinert solvent used in the halogenation, for example, tetrahydrofuran,dichloromethane, acetic acid, toluene, N,N-dimethylformamide, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 10 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process ε

A compound represented by the above general formula (XXIX) can beprepared by introducing a hydroxy-protective group to a compoundrepresented by the above general formula (XXXVII) using ahydroxy-protecting agent such as benzyl bromide or chloromethyl methylether in the presence or absence of a base in an inert solvent. As theinert solvent used in the introducing reaction, for example, toluene,tetrahydrofuran, dichloromethane, N,N-dimethylformamide, ethanol, water,a mixed solvent thereof and the like can be illustrated. As the base,for example, sodium hydride, sodium amide, sodium carbonate, sodiumethoxide, triethylamine, imidazole and the like can be illustrated. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Process ζ

A compound represented by the above general formula (XXXVIII) can beprepared by introducing a hydroxy-protective group to a compoundrepresented by the above general formula (XXXVI) using ahydroxy-protecting agent such as benzyl bromide or chloromethyl methylether in the presence or absence of a base in an inert solvent. As theinert solvent used in the introducing reaction, for example, toluene,tetrahydrofuran, dichloromethane, N,N-dimethylformamide, ethanol, water,a mixed solvent thereof and the like can be illustrated. As the base,for example, sodium hydride, sodium amide, sodium carbonate, sodiumethoxide, triethylamine, imidazole and the like can be illustrated. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Process η

A compound represented by the above general formula (XXIX) can beprepared by halogenating a compound represented by the above generalformula (XXXVIII) using a halogenating agent such as bromine or iodineafter treating with a base such as n-butyllithium in an inert solvent.As the inert solvent used in the halogenation, for example, toluene,tetrahydrofuran, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from −78° C. to refluxtemperature, and the reaction time is usually from 10 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Among the compounds represented by the above general formula (III) ofthe present invention, there can be the following tautomers in compoundswherein T^(B) is a hydroxy group, varying based on difference in thereactions, and both of the compounds are included in the presentinvention.

Among the compounds represented by the above general formula (III) ofthe present invention, there can be the following tautomers in compoundswherein Q^(B) is a hydroxy group, varying based on difference in thereactions, and both of the compounds are included in the presentinvention:

In addition, among the compounds represented by the above generalformula (III) of the present invention, there can be the followingtautomers in compounds wherein R^(1A) is a hydrogen atom, varying basedon difference in the reactions, and all the compounds are included inthe present invention:

The compounds represented by the above general formula (I) or (I′) ofthe present invention obtained by the above production processes can beisolated and purified by conventional separation means such asfractional recrystallization, purification using chromatography, solventextraction and solid phase extraction.

The pyrazole derivatives represented by the above general formula (I) ofthe present invention can be converted into their pharmaceuticallyacceptable salts in the usual way. Examples of such salts include acidaddition salts with mineral acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid andthe like, acid addition salts with organic acids such as formic acid,acetic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, propionic acid, citric acid, succinic acid,tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid,maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid,aspartic acid and the like, salts with inorganic bases such as a sodiumsalt, a potassium salt and the like, and salts with organic bases suchas N-methyl-D-glucamine, N,N′-dibenzyletylenediamine, 2-aminoethanol,tris(hydroxymethyl)aminomethane, arginine, lysine and the like.

The compounds represented by the above general formula (I) of thepresent invention or pharmaceutically acceptable salts thereof, orprodrugs thereof include their solvates with pharmaceutically acceptablesolvents such as ethanol and water.

Of the pyrazole derivatives represented by the above general formula (I)of the present invention and the prodrugs thereof, there are twogeometrical isomers in each compound having an unsaturated bond. In thepresent invention, either of cis(Z)-isomer or trans(E)-isomer can beemployed.

Of the pyrazole derivatives represented by the above general formula (I)of the present invention and the prodrugs thereof, there are two opticalisomers, R-isomer and S-isomer, in each compound having an asymmetriccarbon atom excluding the sugar moiety of glucopyranosyloxy,mannopyranosyloxy and 2-deoxyglucopyranosyloxy moieties. In the presentinvention, either of the isomers can be employed, and a mixture of bothisomers can be also employed. In addition, there can be two rotationalisomers in each compound having a rotational barrier. In the presentinvention, either of the isomers can be employed, and a mixture of bothisomers can be also employed.

A prodrug of a compound represented by the above general formula (I) ofthe present invention can be prepared by introducing an appropriategroup forming a prodrug into any one or more groups selected from ahydroxy group in a sugar moiety of glucopyranosyloxy, mannopyranosyloxyand 2-deoxyglucopyranosyloxy moieties, as the case may be a hydroxygroup in R, R¹, Q or T, a cyclic amino group in case that R¹ is ahydrogen atom, an optionally mono(C₁₋₆ alkyl)-substituted amino group incase that R, R¹, Q or T is a substituent having an amino group or amono(C₁₋₆ alkyl)amino group, a thiol group and a sulfonamide group ofthe compound represented by the above general formula (I) using acorresponding reagent to produce a prodrug such as a halide compound orthe like in the usual way, and then by suitably isolating andpurificating in the usual way as occasion demands. As a group forming aprodrug used in a hydroxy group, for example, a C₂₋₂₀ acyl group, a C₁₋₆alkoxy-substituted (C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl-substituted(C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl group, a C₁₋₆alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group, a benzoyl group, a (C₂₋₇acyloxy)methyl group, a 1-(C₂₋₇ acyloxy)ethyl group, a (C₂₋₇alkoxycarbonyl)-oxymethyl group, a 1-[( C₂₋₇ alkoxycarbonyl)oxy]ethylgroup, a (C₃₋₇ cycloalkyl)oxycarbonyloxymethyl group, a 1-[(C₃₋₇cycloalkyl)oxycarbonyloxy]ethyl group, an ester group condensed with anamino acid, a phosphoric acid derivative or a cinnamic acid derivativeor the like can be illustrated. As a group forming a prodrug used in anamino group, for example, a C₂₋₇ acyl group, a C₁₋₆ alkoxy-substituted(C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl-substituted (C₂₋₇ acyl) group,a C₂₋₇ alkoxycarbonyl group, a C₁₋₆ alkoxy-substituted (C₂₋₇alkoxycarbonyl) group, a benzoyl group, a (C₂₋₇ acyloxy)methyl group, a1-(C₂₋₇ acyloxy)ethyl group, a (C₂₋₇ alkoxycarbonyl)-oxymethyl group, a1-[(C₂₋₇ alkoxycarbonyl)oxy]ethyl group, a (C₃₋₇cycloalkyl)oxycarbonyloxymethyl group, a 1-[(C₃₋₇cycloalkyl)oxycarbonyloxy]ethyl group, an amide group condensed with anamino acid or the like can be illustrated. As a group forming a prodrugused in a cyclic amino group, for example, a C₂₋₇ acyl group, a C₁₋₆alkoxy-substituted (C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl-substituted(C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl group, a C₁₋₆alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group, a (C₂₋₇ acyloxy)methylgroup, a 1-(C₂₋₇ acyloxy)ethyl group, a (C₂₋₇ alkoxycarbonyl)oxymethylgroup, a 1-[(C₂₋₇ alkoxycarbonyl)oxy]ethyl group, a (C₃₋₇cycloalkyl)oxycarbonyloxymethyl group, a 1-[(C₃₋₇cycloalkyl)-oxycarbonyloxylethyl group, a benzoyl group or the like canbe illustrated. As a group forming a prodrug used in a thiol group, forexample, a C₂₋₂₀ acyl group, a C₁₋₆ alkoxy-substituted (C₂₋₇ acyl)group, a C₂₋₇ alkoxycarbonyl-substituted (C₂₋₇ acyl) group, a C₂₋₇alkoxycarbonyl group, a C₁₋₆ alkoxy-substituted (C₂₋₇ alkoxycarbonyl)group, a benzoyl group, a (C₂₋₇ acyloxy)methyl group, a 1-(C₂₋₇acyloxy)ethyl group, a (C₂₋₇ alkoxycarbonyl)-oxymethyl group, a 1-[(C₂₋₇alkoxycarbonyl)oxy]ethyl group, a (C₃₋₇ cycloalkyl)oxycarbonyloxymethylgroup, a 1-[(C₃₋₇ cycloalkyl)oxycarbonyloxy]ethyl group, an ester groupcondensed with an amino acid, a phosphoric acid derivative or a cinnamicacid derivative or the like can be illustrated. As a group forming aprodrug used in a sulfonamide group, for example, a (C₂₋₇ acyloxy)methylgroup, a 1-(C₂₋₇ acyloxy)ethyl group, a (C₂₋₇ alkoxycarbonyl)oxymethylgroup, a 1-[(C₂₋₇ alkoxycarbonyl)oxy]ethyl group, a (C₃₋₇cycloalkyl)oxycarbonyloxymethyl group, a 1-[(C₃₋₇cycloalkyl)oxycarbonyloxy]ethyl group or the like can be illustrated.The term “C₂₋₇ acyl group” means a straight-chained or branched acylgroup having 2 to 7 carbon atoms such as an acetyl group, a propionylgroup, a butyryl group, an isobutyryl group, a valeryl group, a pivaloylgroup, a hexanoyl group or the like; the term “C₂₋₂₀ acyl group” means astraight-chained or branched acyl group having 2 to 20 carbon atoms suchas an acetyl group, a propionyl group, a butyryl group, an isobutyrylgroup, a valeryl group, a pivaloyl group, a hexanoyl group, a lauroylgroup, a myristoyl group, a palmitoyl group, a stearoyl group or thelike; the term “C₁₋₆ alkoxy-substituted (C₂₋₇ acyl) group” means theabove C₂₋₇ acyl group substituted by the above C₁₋₆ alkoxy group; theterm “C₂₋₇ alkoxycarbonyl group” means a straight-chained or branchedalkoxycarbonyl group having 2 to 7 carbon atoms such as amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,an isopropoxycarbonyl group, a butoxycarbonyl group, anisobutyloxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group, a pentyloxycarbonyl group, anisopentyloxycarbonyl group, a neopentyloxycarbonyl group, atert-pentyloxycarbonyl group, a hexyloxycarbonyl group or the like or acyclic alkoxycarbonyl group having a 3 to 6-membered cycloalkyl groupsuch as a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, acyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group or the like;the term “C₂₋₇ alkoxycarbonyl-substituted (C₂₋₇ acyl) group” means theabove C₂₋₇ acyl group substituted by the above C₂₋₇ alkoxycarbonylgroup; the term “C₁₋₆ alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group”means the above C₂₋₇ alkoxycarbonyl group substituted by the above C₁₋₆alkoxy group; the term “(C₂₋₇ acyloxy)methyl group” means ahydroxymethyl group O-substituted by the above C₂₋₇ acyl group; the term“1-(C₂₋₇ acyloxy)ethyl group” means a 1-hydroxyethyl group O-substitutedby the above C₂₋₇ acyl group; the term “(C₂₋₇ alkoxycarbonyl)oxymethylgroup” means a hydroxymethyl group O-substituted by the above C₂₋₇alkoxy-carbonyl group; and the term 1-[(C₂₋₇ alkoxycarbonyl)oxy]ethylgroup” means a 1-hydroxyethyl group O-substituted by the above C₂₋₇alkoxycarbonyl group. In addition, the term “(C₃₋₇cycloalkyl)oxycarbonyl group” means an ester group having the above C₃₋₇cycloalkyl group; the term “(C₃₋₇ cycloalkyl)-oxycarbonyloxymethylgroup” means a hydroxymethyl group O-substituted by the above (C₃₋₇cycloalkyl)oxycarbonyl group; and the term 1-[(C₃₋₇cycloalkyl)oxycarbonyloxylethyl group” means a 1-hydroxyethyl groupO-substituted by the above (C₃₋₇ cycloalkyl)oxycarbonyl group.Furthermore, as a group forming a prodrug, a sugar residue of aglucopyranosyl group, a galactopyranosyl group or the like can beillustrated. For example, these groups are preferably introduced intothe hydroxy group at the 4 or 6 position of the sugar moiety ofglucopyranosyloxy group or the like.

The pyrazole derivatives represented by the above general formula (I) ofthe present invention, for example, showed a potent inhibitory activityin human 1,5-anhydroglucitol/fructose/mannose transporter inhibitoryactivity confirmatory test as described below. Thus, the pyrazolederivatives represented by the above general formula (I) of the presentinvention exhibit an excellent inhibitory activity on1,5-anhydroglucitol/fructose/mannose transporter found highly in thekidney and small intestine, and can remarkably inhibit blood glucoselevel increase by inhibiting the reabsorption at the kidney or uptakeinto cells of glucose, mannose and fructose or inhibiting the sugarabsorption in the small intestine. Therefore, a pyrazole derivativerepresented by the above general formula (I) of the present invention, apharmaceutically acceptable salt and a prodrug thereof is extremelyuseful as an agent for prevention or inhibition of progression of adisease associated with the excess uptake of at least a kind ofcarbohydrates selected from glucose, fructose and mannose or a diseaseassociated with hyperglycemia such as diabetic complications (e.g.retinopathy, neuropathy, nephropathy, ulcer, macroangiopathy), diabetes,impaired glucose tolerance, obesity, hyperinsulinemia, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder,atherosclerosis, hypertension, congestive heart failure, edema,hyperuricemia, gout or the like, especially for prevention or inhibitionof progression of diabetic complications such as diabetic nephropathy.

Furthermore, the compounds of the present invention can be suitably usedin combination with at least one member selected from drugs other than1,5-anhydroglucitol/fructose/mannose transporter inhibitors. Examples ofthe drugs which can be used in combination with the compounds of thepresent invention include an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer, aSGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation end products formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptorantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor (PDGF), a platelet-derivedgrowth factor (PDGF) analogue (e.g., PDGF-AA, PDGF-BB, PDGF-AB),epidermal growth factor (EGF), nerve growth factor, a carnitinederivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol,sulodexide, Y-128, a hydroxymethylglutaryl coenzyme A reductaseinhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, anacyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, athyroid hormone receptor agonist, a cholesterol absorption inhibitor, alipase inhibitor, a microsomal triglyceride transfer protein inhibitor,a lipoxygenase inhibitor, a carnitine palmitoyl transferase inhibitor, asqualene synthase inhibitor, a low-density lipoprotein receptorenhancer, a nicotinic acid derivative, a bile acid sequestrant, asodium/bile acid cotransporter inhibitor, a cholesterol ester transferprotein inhibitor, an appetite suppressant, an angiotensin-convertingenzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin IIreceptor antagonist, an endothelin-converting enzyme inhibitor, anendothelin receptor antagonist, a diuretic agent, a calcium antagonist,a vasodilating antihypertensive agent, a sympathetic blocking agent, acentrally acting antihypertensive agent, an α₂-adrenoceptor agonist, anantiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agentand a urinary alkalinizer.

In case of uses of the compound of the present invention in combinationwith the above one or more drugs, the present invention includes eitherdosage forms of simultaneous administration as a single preparation orseparated preparations in way of the same or different administrationroute, and administration at different dosage intervals as separatedpreparations in way of the same or different administration route. Apharmaceutical combination comprising the compound of the presentinvention and the above drug(s) includes both dosage forms as a singlepreparation and separated preparations for combination as mentionedabove.

The compounds of the present invention can obtain more advantageouseffects than additive effects in the prevention or treatment of theabove diseases when using suitably in combination with the above one ormore drugs. Also, the administration dose can be decreased in comparisonwith administration of either drug alone, or adverse effects ofcoadministrated drugs other than 1,5-anhydroglucitol/fructose/mannosetransporter inhibitors can be avoided or declined.

Concrete compounds as the drugs used for combination and preferablediseases to be treated are exemplified as follows. However, the presentinvention is not limited thereto, and the concrete compounds includetheir free compounds, and their or other pharmaceutically acceptablesalts.

As insulin sensitivity enhancers, peroxisome proliferator-activatedreceptor-γagonists such as troglitazone, pioglitazone hydrochloride,rosiglitazone maleate, sodium darglitazone, GI-262570, isaglitazone,LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929,ciglitazone, sodium englitazone and NIP-221, peroxisomeproliferator-activated receptor-αagonists such as GW-9578 and BM-170744,peroxisome proliferator-activated receptor-α/γagonists such asGW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158 andDRF-MDX8, retinoid X receptor agonists such as ALRT-268, AGN-4204,MX-6054, AGN-194204, LG-100754 and bexarotene, and other insulinsensitivity enhancers such as reglixane, ONO-5816, MBX-102, CRE-1625,FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975,CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929,AR-H049020 and GW-501516 are illustrated. Insulin sensitivity enhancersare used preferably for diabetes, impaired glucose tolerance, diabeticcomplications, obesity, hyperinsulinemia, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder oratherosclerosis, and more preferably for diabetes, impaired glucosetolerance or hyperinsulinemia because of improving the disturbance ofinsulin signal transduction in peripheral tissues and enhancing glucoseuptake into the tissues from the blood, leading to lowering of bloodglucose level.

As glucose absorption inhibitors, for example, α-glucosidase inhibitorssuch as acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25,637,camiglibose and MDL-73,945, α-amylase inhibitors such as AZM-127, andSGLT1 inhibitors are illustrated. Glucose absorption inhibitors are usedpreferably for diabetes, impaired glucose tolerance, diabeticcomplications, obesity or hyperinsulinemia, and more preferably forimpaired glucose tolerance because of inhibiting the gastrointestinalenzymatic digestion of carbohydrates contained in foods, and inhibitingor delaying the absorption of glucose into the body.

As biguanides, phenformin, buformin hydrochloride, metforminhydrochloride or the like are illustrated. Biguanides are usedpreferably for diabetes, impaired glucose tolerance, diabeticcomplications or hyperinsulinemia, and more preferably for diabetes,impaired glucose tolerance or hyperinsulinemia because of lowering bloodglucose level by inhibitory effects on hepatic gluconeogenesis,accelerating effects on anaerobic glycolysis in tissues or improvingeffects on insulin resistance in peripheral tissues.

As insulin secretion enhancers, tolbutamide, chlorpropamide, tolazamide,acetohexamide, glyclopyramide, glyburide (glibenclamide), gliclazide,1-butyl-3-metanilylurea, carbutamide, glibornuride, glipizide,gliquidone, glisoxapide, glybuthiazol, glybuzole, glyhexamide, sodiumglymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride,nateglinide, mitiglinide calcium hydrate, repaglinide or the like areillustrated. Insulin secretion enhancers are used preferably fordiabetes, impaired glucose tolerance or diabetic complications, and morepreferably for diabetes or impaired glucose tolerance because oflowering blood glucose level by acting on pancreatic β-cells andenhancing the insulin secretion.

As SGLT2 inhibitors, T-1095 and compounds described in Japanese patentpublications Nos. Hei 10-237089 and 2001-288178, and InternationalPublications Nos. WO01/16147, WO01/27128, WO01/68660, WO01/74834,WO01/74835, WO02/28872, WO02/36602, WO02/44192, WO02/053573,WO02/064606, WO02/068439, WO02/068440 or the like are illustrated. SGLT2inhibitors are used preferably for diabetes, impaired glucose tolerance,diabetic complications, obesity or hyperinsulinemia, and more preferablyfor diabetes, impaired glucose tolerance, obesity or hyperinsulinemiabecause of lowering blood glucose level by inhibiting the reabsorptionof glucose at the kidney's proximal tubule.

As insulin or insulin analogues, human insulin, animal-derived insulin,human or animal-derived insulin analogues or the like are illustrated.These preparations are used preferably for diabetes, impaired glucosetolerance or diabetic complications, and more preferably for diabetes orimpaired glucose tolerance.

As glucagon receptor antagonists, BAY-27-9955, NNC-92-1687 or the likeare illustrated; as insulin receptor kinase stimulants, TER-17411,L-783281, KRX-613 or the like are illustrated; as tripeptidyl peptidaseII inhibitors, UCL-1397 or the like are illustrated; as dipeptidylpeptidase IV inhibitors, NVP-DPP728A, TSL-225, P-32/98 or the like areillustrated; as protein tyrosine phosphatase 1B inhibitors, PTP-112,OC-86839, PNU-177496 or the like are illustrated; as glycogenphosphorylase inhibitors, NN-4201, CP-368296 or the like areillustrated; as fructose-bisphosphatase inhibitors, R-132917 or the likeare illustrated; as pyruvate dehydrogenase inhibitors, AZD-7545 or thelike are illustrated; as hepatic gluconeogenesis inhibitors, FR-225659or the like are illustrated; as glucagon-like peptide-1 analogues,exendin-4, CJC-1131 or the like are illustrated; as glucagon-likepeptide 1 agonists; AZM-134, LY-315902 or the like are illustrated; andas amylin, amylin analogues or amylin agonists, pramlintide acetate orthe like are illustrated. These drugs, glucose-6-phosphatase inhibitors,D-chiroinsitol, glycogen synthase kinase-3 inhibitors and glucagon-likepeptide-1 are used preferably for diabetes, impaired glucose tolerance,diabetic complications or hyperinsulinemia, and more preferably fordiabetes or impaired glucose tolerance.

As aldose reductase inhibitors, ascorbyl gamolenate, tolrestat,epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598,fidarestat, sorbinil, ponalrestat, risarestat, zenarestat, minalrestat,methosorbinil, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat,AS-3201, NZ-314, SG-210, JTT-811, lindolrestat or the like areillustrated. Aldose reductase inhibitors are preferably used fordiabetic complications because of inhibiting aldose reductase andlowering excessive intracellular accumulation of sorbitol in acceleratedpolyol pathway which are in continuous hyperglycemic condition in thetissues in diabetic complications.

As advanced glycation end products formation inhibitors, pyridoxamine,OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride or the like areillustrated. Advanced glycation end products formation inhibitors arepreferably used for diabetic complications because of inhibitingformation of advanced glycation end products which are accelerated incontinuous hyperglycemic condition in diabetes and declining of cellulardamage.

As protein kinase C inhibitors, LY-333531, midostaurin or the like areillustrated. Protein kinase C inhibitors are preferably used fordiabetic complications because of inhibiting of protein kinase Cactivity which is accelerated in continuous hyperglycemic condition indiabetes.

As γ-aminobutyric acid receptor antagonists, topiramate or the like areillustrated; as sodium channel antagonists, mexiletine hydrochloride,oxcarbazepine or the like are illustrated; as transcrit factor NF-κBinhibitors, dexlipotam or the like are illustrated; as lipid peroxidaseinhibitors, tirilazad mesylate or the like are illustrated; asN-acetylated-α-linked-acid-dipeptidase inhibitors, GPI-5693 or the likeare illustrated; and as carnitine derivatives, carnitine, levacecarninehydrochloride, levocarnitine chloride, levocarnitine, ST-261 or the likeare illustrated. These drugs, insulin-like growth factor-I,platelet-derived growth factor, platelet derived growth factoranalogues, epidermal growth factor, nerve growth factor, uridine,5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide and Y-128are preferably used for diabetic complications.

As hydroxymethylglutaryl coenzyme A reductase inhibitors, sodiumcerivastatin, sodium pravastatin, lovastatin, simvastatin, sodiumfluvastatin, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101,BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987,calcium pitavastatin, calcium rosuvastatin, colestolone, dalvastatin,acitemate, mevastatin, crilvastatin, BMS-180431, BMY-21950,glenvastatin, carvastatin, BMY-22089, bervastatin or the like areillustrated. Hydroxymethylglutaryl coenzyme A reductase inhibitors areused preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypercholesterolemia oratherosclerosis because of lowering blood cholesterol level byinhibiting hydroxymethylglutaryl coenzyme A reductase.

As fibric acid derivatives, bezafibrate, beclobrate, binifibrate,ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibricacid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate,ronifibrate, simfibrate, theofibrate, AHL-157 or the like areillustrated. Fibric acid derivatives are used preferably forhyperinsulinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypertriglyceridemia oratherosclerosis because of activating hepatic lipoprotein lipase andenhancing fatty acid oxidation, leading to lowering of bloodtriglyceride level.

As β₃-adrenoceptor agonists, BRL-28410, SR-58611A, ICI-198157, ZD-2079,BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413,SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552,D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353,N-5984, GW-2696, YM178 or the like are illustrated. β₃-Adrenoceptoragonists are used preferably for obesity, hyperinsulinemia,hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipidmetabolism disorder, and more preferably for obesity or hyperinsulinemiabecause of stimulating β₃-adrenoceptor in adipose tissue and enhancingthe fatty acid oxidation, leading to induction of energy expenditure.

As acyl-coenzyme A cholesterol acyltransferase inhibitors, NTE-122,MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139,CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115,FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8-434, avasimibe,CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E,lecimibide, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe or thelike are illustrated. Acyl-coenzyme A cholesterol acyltransferaseinhibitors are used preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia or lipid metabolism disorder, and more preferablyfor hyperlipidemia or hypercholesterolemia because of lowering bloodcholesterol level by inhibiting acyl-coenzyme A cholesterolacyltransferase.

As thyroid hormone receptor agonists, sodium liothyronine, sodiumlevothyroxine, KB-2611 or the like are illustrated; as cholesterolabsorption inhibitors, ezetimibe, SCH-48461 or the like are illustrated;as lipase inhibitors, orlistat, ATL-962, AZM-131, RED-103004 or the likeare illustrated; as carnitine palmitoyl transferase inhibitors, etomoxiror the like are illustrated; as squalene synthase inhibitors,SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393,ER-27856 or the like are illustrated; as nicotinic acid derivatives,nicotinic acid, nicotinamide, nicomol, niceritrol, acipimox, nicorandilor the like are illustrated; as bile acid sequestrants, colestyramine,colestilan, colesevelam hydrochloride, GT-102-279 or the like areillustrated; as sodium/bile acid cotransporter inhibitors, 264W94,S-8921, SD-5613 or the like are illustrated; and as cholesterol estertransfer protein inhibitors, PNU-107368E, SC-795, JTT-705, CP-529414 orthe like are illustrated. These drugs, probcol, microsomal triglyceridetransfer protein inhibitors, lipoxygenase inhibitors and low-densitylipoprotein receptor enhancers are preferably used for hyperlipidemia,hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorder.

As appetite suppressants, monoamine reuptake inhibitors, serotoninreuptake inhibitors, serotonin releasing stimulants, serotonin agonists(especially 5HT_(2C)-agonists), noradrenaline reuptake inhibitors,noradrenaline releasing stimulants, α₁-adrenoceptor agonists,β₂-adrenoceptor agonists, dopamine agonists, cannabinoid receptorantagonists, γ-aminobutyric acid receptor antagonists, H₃-histamineantagonists, L-histidine, leptin, leptin analogues, leptin receptoragonists, melanocortin receptor agonists (especially, MC3-R agonists,MC4-R agonists), α-melanocyte stimulating hormone, cocaine-andamphetamine-regulated transcript, mahogany protein, enterostatinagonists, calcitonin, calcitonin-gene-related peptide, bombesin,cholecystokinin agonists (especially CCK-A agonists),corticotropin-releasing hormone, corticotrophin-releasing hormoneanalogues, corticotropin-releasing hormone agonists, urocortin,somatostatin, somatostatin analogues, somatostatin receptor agonists,pituitary adenylate cyclase-activating peptide, brain-derivedneurotrophic factor, ciliary neurotrophic factor, thyrotropin-releasinghormone, neurotensin, sauvagine, neuropeptide Y antagonists, opioidpeptide antagonists, galanin antagonists, melanin-concentrating hormoneantagonists, agouti-related protein inhibitors and orexin receptorantagonists are illustrated. Concretely, as monoamine reuptakeinhibitors, mazindol or the like are illustrated; as serotonin reuptakeinhibitors, dexfenfluramine hydrochloride, fenfluramine, sibutraminehydrochloride, fluvoxamine maleate, sertraline hydrochloride or the likeare illustrated; as serotonin agonists, inotriptan, (+)-norfenfluramineor the like are illustrated; as noradrenaline reuptake inhibitors,bupropion, GW-320659 or the like are illustrated; as noradrenalinereleasing stimulants, rolipram, YM-992 or the like are illustrated; asβ₂-adrenoceptor agonists, amphetamine, dextroamphetamine, phentermine,benzphetamine, methamphetamine, phendimetrazine, phenmetrazine,diethylpropion, phenylpropanolamine, clobenzorex or the like areillustrated; as dopamine agonists, ER-230, doprexin, bromocriptinemesylate or the like are illustrated; as cannabinoid receptorantagonists, rimonabant or the like are illustrated; as γ-aminobutyricacid receptor antagonists, topiramate or the like are illustrated; asH₃-histamine antagonists, GT-2394 or the like are illustrated; asleptin, leptin analogues or leptin receptor agonists, LY-355101 or thelike are illustrated; as cholecystokinin agonists (especially CCK-Aagonists), SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849,GI-248573, GW-7178, GI-181771, GW-7854, A-71378 or the like areillustrated; and as neuropeptide Y antagonists, SR-120819-A, PD-160170,NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01,J-115814 or the like are illustrated. Appetite suppressants are usedpreferably for diabetes, impaired glucose tolerance, diabeticcomplications, obesity, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,hypertension, congestive heart failure, edema, hyperuricemia or gout,and more preferably for obesity because of stimulating or inhibiting theactivities of intracerebral monoamines or bioactive peptides in centralappetite regulatory system and suppressing the appetite, leading toreduction of energy intake.

As angiotensin-converting enzyme inhibitors, captopril, enalaprimaleate, alacepril, delapril hydrochloride, ramipril, lisinopril,imidapril hydrochloride, benazepril hydrochloride, ceronaprilmonohydrate, cilazapril, sodium fosinopril, perindopril erbumine,calcium moveltipril, quinapril hydrochloride, spirapril hydrochloride,temocapril hydrochloride, trandolapril, calcium zofenopril, moexiprilhydrochloride, rentiapril or the like are illustrated.Angiotensin-converting enzyme inhibitors are preferably used fordiabetic complications or hypertension.

As neutral endopeptidase inhibitors, omapatrilat, MDL-100240,fasidotril, sampatrilat, GW-660511X, mixanpril, SA-7060, E-4030,SLV-306, ecadotril or the like are illustrated. Neutral endopeptidaseinhibitors are preferably used for diabetic complications orhypertension.

As angiotensin II receptor antagonists, candesartan cilexetil,candesartan cilexetil/hydrochlorothiazide, potassium losartan,eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174,L-158809, EXP-3312, olmesartan, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701 or the like are illustrated. Angiotensin II receptorantagonists are preferably used for diabetic complications orhypertension.

As endothelin-converting enzyme inhibitors, CGS-31447, CGS-35066,SM-19712 or the like are illustrated; as endothelin receptorantagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355,PD-180988, sodium sitaxsentan, BMS-193884, darusentan, TBC-3711,bosentan, sodium tezosentan, J-104132, YM-598, S-0139, SB-234551,RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940 orthe like are illustrated. These drugs are preferably used for diabeticcomplications or hypertension, and more preferably for hypertension.

As diuretic agents, chlorthalidone, metolazone, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, methyclothiazide, indapamide,tripamide, mefruside, azosemide, etacrynic acid, torasemide, piretanide,furosemide, bumetanide, meticrane, potassium canrenoate, spironolactone,triamterene, aminophylline, cicletanine hydrochloride, LLU-α,PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin,acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan,conivaptan hydrochloride or the like are illustrated. Diuretic drugs arepreferably used for diabetic complications, hypertension, congestiveheart failure or edema, and more preferably for hypertension, congestiveheart failure or edema because of reducing blood pressure or improvingedema by increasing urinary excretion.

As calcium antagonists, aranidipine, efonidipine hydrochloride,nicardipine hydrochloride, barnidipine hydrochloride, benidipinehydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine,nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besilate,pranidipine, lercanidipine hydrochloride, isradipine, elgodipine,azelnidipine, lacidipine, vatanidipine hydrochloride, lemildipine,diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride,S-verapamil, fasudil hydrochloride, bepridil hydrochloride, gallopamilhydrochloride or the like are illustrated; as vasodilatingantihypertensive agents, indapamide, todralazinehydrochloride,hydralazine hydrochloride, cadralazine, budralazine or the like areillustrated; as sympathetic blocking agents, amosulalol hydrochloride,terazosin hydrochloride, bunazosin hydrochloride, prazosinhydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol,metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride,nebivolol, betaxolol hydrochloride, pindolol, tertatolol hydrochloride,bevantolol hydrochloride, timolol maleate, carteolol hydrochloride,bisoprolol hemifumarate, bopindolol malonate, nipradilol, penbutololsulfate, acebutolol hydrochloride, tilisolol hydrochloride, nadolol,urapidil, indoramin or the like are illustrated; as centrally actingantihypertensive agents, reserpine or the like are illustrated; and asα₂-adrenoceptor agonists, clonidine hydrochloride, methyldopa, CHF-1035,guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine,talipexole hydrochloride or the like are illustrated. These drugs arepreferably used for hypertension.

As antiplatelets agents, ticlopidine hydrochloride, dipyridamole,cilostazol, ethyl icosa pentate, sarpogrelate hydrochloride, dilazepdihydrochloride, trapidil, beraprost sodium, aspirin or the like areillustrated. Antiplatelets agents are preferably used foratherosclerosis or congestive heart failure.

As uric acid synthesis inhibitors, allopurinol, oxypurinol or the likeare illustrated; as uricosuric agents, benzbromarone, probenecid or thelike are illustrated; and as urinary alkalinizers, sodium hydrogencarbonate, potassium citrate, sodium citrate or the like areillustrated. These drugs are preferably used for hyperuricemia or gout.

In case of uses in combination with drugs other than1,5-anhydroglucitol/fructose/mannose transporter inhibitors, forexample, in the use for diabetic complications, the combination with atleast one member of the group consisting of an insulin sensitivityenhancer, a glucose absorption inhibitor, a biguanide, an insulinsecretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, aglucagon receptor antagonist, an insulin receptor kinase stimulant, atripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor,a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylaseinhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphataseinhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesisinhibitor, D-chiroinsitol, glycogen synthase kinase-3 inhibitors,glucagon-like peptide-1, a glucagon-like peptide-1 analogue, aglucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylinagonist, an aldose reductase inhibitor, an advanced glycation endproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, alipidperoxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, an angiotensin-converting enzymeinhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptorantagonist, an endothelin-converting enzyme inhibitor, an endothelinreceptor antagonist and a diuretic agent is preferable; and thecombination with at least one member of the group consisting of analdose reductase inhibitor, an angiotensin-converting enzyme inhibitor,a neutral endopeptidase inhibitor and an angiotensin II receptorantagonist is more preferable. Similarly, in the use for diabetes, thecombination with at least one member of the group consisting of aninsulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, a SGLT2 inhibitors, an insulinor insulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructosebisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist and an appetite suppressant is preferable; thecombination with at least one member of the group consisting of aninsulin sensitivity enhancer, a biguanide, an insulin secretionenhancer, a SGLT2 inhibitors, an insulin or insulin analogue, a glucagonreceptor antagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue and an amylin agonist is morepreferable; and the combination with at least one member of the groupconsisting of an insulin sensitivity enhancer, a biguanide, an insulinsecretion enhancer, a SGLT2 inhibitor and an insulin or insulin analogueis most preferable. Furthermore, in the use for obesity, the combinationwith at least one member of the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, a β₃-adrenoceptor agonist and an appetite suppressantis preferable; and the combination with at least one member of the groupconsisting of a SGLT2 inhibitor, a β₃-adrenoceptor agonist and anappetite suppressant is more preferable.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry syrups, tablets, capsules, topical dosages(e.g., transdermal absorption preparations), injections, suppositories,solutions and the like are illustrated, which are orally or parenterallyadministered. The pharmaceutical compositions of the present inventioncan also include sustained release formulation and enteric coatedpreparation.

These pharmaceutical compositions can be prepared optionally byadmixing, diluting, dissolving and then coating using an appropriatepharmaceutical additive such as excipients, disintegrators, binders,lubricants, diluents, buffers, isotonicities, antiseptics, moisteningagents, emulsifiers, dispersing agents, stabilizing agents, dissolvingaids, viscosity-increasing agents, gelling agents, hardening agents,absorbents, viscosing agents, elasticating agents, plasticizers, coatingagents, sustained-releasing agent, antioxidants, light shielding agents,antistatic agents, fragrances, sweetening agents, flavors, coloringagents, soothing agents and the like, and formulating the mixture inaccordance with conventional methods. In case of the uses of thecompound of the present invention in combination with the drug(s) otherthan 1,5-anhydroglucitol/fructose/mannose transporter inhibitors, theycan be prepared by formulating each active ingredient together orindividually.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a compoundrepresented by the above general formula (I), or a pharmaceuticallyacceptable salt thereof or a prodrug thereof as the active ingredient isappropriately decided depending on the age, sex, body weight and degreeof symptoms and treatment of each patient, which is approximately withinthe range of from 0.1 to 1,000 mg per day per adult human in the case oforal administration and approximately within the range of from 0.01 to300 mg per day per adult human in the case of parenteral administration,and the daily dose can be divided into one to several doses per day andadministered suitably. Also, in case of the uses of the compound of thepresent invention in combination with the drug(s) other than1,5-anhydroglucitol/fructose/mannose transporter inhibitors, the dosageof the compound of the present invention can be decreased, depending onthe dosage of the drug(s) other than1,5-anhydroglucitol/fructose/mannose transporter inhibitors.

In addition, the present invention also includes a screening method foran agent for the prevention, inhibition of progression or treatment of adisease associated with the excess uptake of at least a kind ofcarbohydrates selected from glucose, fructose and mannose, characterizedby using a protein relating to 1,5-anhydroglucitol/fructose/mannosetransporter.

The present invention includes a screening method for an agent for theprevention or inhibition of progression of diabetic complications suchas diabetic nephropathy, characterized by using a protein relating to1,5-anhydroglucitol/fructose/mannose transporter.

The present invention also includes an agent for prevention, inhibitionof progression or treatment of a disease associated with the excessuptake of at least a kind of carbohydrates selected from glucose,fructose and mannose, comprising as an active ingredient an inhibitor of1,5-anhydroglucitol/fructose/mannose transporter.

The present invention includes an agent for prevention or inhibition ofprogression of diabetic complications such as diabetic nephropathy,comprising as an active ingredient an inhibitor of1,5-anhydroglucitol/fructose/mannose transporter.

Furthermore, the present invention includes an agent for prevention,inhibition of progression or treatment of a disease associated withhyperglycemia such as diabetes, comprising as an active ingredient aninhibitor of 1,5-anhydroglucitol/fructose/mannose transporter.

The details are illustrated below regarding the screening method for anagent for the prevention, inhibition of progression or treatment of adisease associated with the excess uptake of at least a kind ofcarbohydrates selected from glucose, fructose and mannose, or an agentfor the prevention or inhibition of progression of diabeticcomplications such as diabetic nephropathy, characterized by using aprotein relating to 1,5-anhydroglucitol/fructose/mannose transporter.

SMINT and SGLTh have 1,5-anhydroglucitol/fructose/mannose transportingactivities. In relative diseases such as diabetic complications,diabetes or obesity in which a flow of carbohydrates, especially glucoseand mannose, have varied with the changes of lifestyles, energyaccumulation in the body is one of contributing factors in pathologicconditions. The 1,5-anhydroglucitol/fructose/mannose transporter relatesto reabsorption in the kidney or uptake into a cell of glucose, fructoseand mannose or absorption in the small intestine of these carbohydrates,and controls the energy flow by controlling the flow of carbohydrates.Therefore, it is considered that the flow of carbohydrate energy can becontrolled by inhibiting 1,5-anhydroglucitol/fructose/mannosetransporter. Thus, an inhibitor of 1,5-anhydroglucitol/fructose/mannosetransporter is useful for prevention, inhibition of progression ortreatment of a disease which pathological conditions are associated withdisturbance in the energy balance, that is, diabetic complications suchas diabetic nephropathy or a disease associated with hyperglycemia.

A screening method of the present invention can be conducted in thefollowing way.

Firstly, DNA molecule encoding the protein with1,5-anhydroglucitol/fructose/mannose transporter activity is ligated toappropriate expression vectors; it is transfected into appropriate hostcells; the cells are cultured under appropriate conditions to expressthe protein of the present invention. As appropriate expression vectorsavailable for expression of the protein to carry out screening, forexample, pCI-neo, pcDNA and pME18S can be illustrated in the case ofanimal cells as host cells; pBluescript II and pGEMEX-1 can beillustrated in the case of Escherichia coli as host cells; pBacPAK8-GUS(transfer vector)/BacPAK6 (virus DNA) and the like can be illustrated inthe case of insect cells as host cells. As appropriate host cells,animal cells such as COS-7 cells, insect cells such as Sf9 cells,prokaryote LB medium (Escherichia coli) such as Escherichia coli and thelike can be illustrated.

Secondly, by using previously prepared cells expressing the protein (forexample, COS-7 cells expressing SMINT and the like), for example, thefollowing operation can be done. First of all, to Uptake Buffercontaining sodium chloride is added methyl-α-D-glucopyranoside as amixture of its non-radiolabeled form and ¹⁴C-labeled form at a finalconcentration of 1 mM. Test compound is dissolved in dimethylsulfoxide,then it is diluted properly with distilled water, and it is added to theUptake Buffer containing 1 mM methyl-α-D-glucopyranoside to prepareAssay Buffer. For control group, Assay Buffer without test compound isprepared; for the determination of basal uptake, Basal Buffer containingcholine chloride instead of sodium chloride of the Uptake Buffer isprepared. Culture medium is removed from cultured cells, andPretreatment Buffer (Basal Buffer without methyl-α-D-glucopyranoside) isadded to the cells, and the cells are incubated at 37° C. for 10minutes. After repeating once the same operation, Pretreatment Buffer isremoved, and each of Assay Buffer and Basal Buffer is added to the cellsfollowed by incubation at 37° C. After 1 hour incubation, the AssayBuffer is removed and the cells are washed twice with Washing Buffer(Basal Buffer containing 10 mM non-radiolabeledmethyl-α-D-glucopyranoside). The cells are lysed with 0.2 mol/L sodiumhydroxide, and the lysate is transferred to PicoPlate. MicroScint 40 isadded to the lysate, and the radioactivity is measured in amicroscintillation counter TOPCOUNT. Methyl-α-D-glucopyranoside uptakeby the cells treated with each concentration of test compounds iscalculated as relative activity to control group, which is set as 100%uptake after deducting the basal uptake. When methyl-α-D-glucopyranosideuptake by the cells treated with a test compound is extremely low orvirtually zero, the test compound is judged to be an effectiveinhibitor.

The above screening method can be optionally modified within commonknowledge of a person skilled in the art. In addition, an agent for theprevention, inhibition of progression or treatment of a diseaseassociated with the excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose; an agent for the preventionor inhibition of progression of diabetic complications such as diabeticnephropathy; or an agent for prevention, inhibition of progression ortreatment of a disease associated with hyperglycemia such as diabetescan be prepared by comprising as an active ingredient an inhibitor of1,5-anhydroglucitol/fructose/mannose transporter of which activity ofinhibiting 1,5-anhydroglucitol/fructose/mannose transporter can beconfirmed by the above screening method or the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the distribution pattern of SMINT geneexpression among human organs. The vertical axis indicates copynumber/ng cDNA, and the horizontal axis indicates the name of humanorgan.

FIG. 2 is a graph showing substrate specificity of human SMINT. Thevertical axis indicates methyl-α-D-glucopyranoside (a-MG) uptakeactivity (%), and the horizontal axis indicates concentration (mol/L).In the graph, an open triangle shows glucose, an open circle showsfructose, a black circle shows galactose, an open square shows mannoseand a black diamond shows 1,5-anhydroglucitol.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is further illustrated in more detail by way ofthe following Examples and Test Examples. However, the present inventionis not limited thereto.

EXAMPLE 1

Process 1

3-(4-Methoxyphenyl)-3-oxothiopropionic acid O-benzyl ester

To a suspension of sodium amide (1.6g) in toluene (50 mL) was added amixture of dithiocarbonic acid O-benzyl ester S-methyl ester (4.0 g) and4-methoxybenzophenone (3.0 g) at room temperature and the mixture wasstirred at room temperature overnight. Hydrochloric acid solution (2mol/L, 80 mL) was added to the reaction mixture and the mixture wasextracted with diethyl ether. The organic layer was washed with brineand dried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane/dichloromethane=5/1-2/1) togive the title compound (3.4 g).

Process 2

3-Benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole

To a suspension of 3-(4-methoxyphenyl)-3-oxothiopropionic acid O-benzylester (0.60 g) and isopropylhydrazine hydrochloride (0.29 g) inacetonitrile (2 mL) was added triethylamine (0.81 g) and the mixture wasstirred at room temperature overnight. Water was added to the reactionmixture and the mixture was extracted with dichloromethane. The solventof the organic layer was removed under reduced pressure and the residuewas purified by column chromatography on silica gel (eluent:hexane/dichloromethane=3/1-1/3) to give the title compound (0.40 g).

¹H-NMR (CDCl₃) δ ppm:

1.41 (6H, d, J=6.6 Hz), 3.85 (3H, s), 4.30-4.45 (1H, m), 5.21 (2H, s),5.63 (1H, s), 6.90-7.00 (2H, m), 7.20-7.40 (5H, m), 7.40-7.55 (2H, m)

Process 3

3-Benzyloxy-4-formyl-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole

To a solution of 3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole(0.40 g) in N,N-dimethylformamide (1.5 mL) was added phosphorusoxychloride (0.23 g) at 80° C. and the mixture was stirred at 80° C. for1 hour. After cooling to room temperature, a sodium hydroxide aqueoussolution (1 mol/L, 5 mL) was added to the reaction mixture and themixture was extracted with diethyl ether. The organic layer was driedover anhydrous magnesium sulfate and the solvent was removed underreduced pressure to give the title compound (0.42 g).

¹H-NMR (CDCl₃) δ ppm:

1.39 (6H, d, J=6.5 Hz), 3.87 (3H, s), 4.25-4.40 (1H, m), 5.41 (2H, s),6.95-7.05 (2H, m), 7.25-7.40 (5H, m), 7.50-7.60 (2H, m), 9.57 (1H, s)

Process 4

[3-Benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl]4-methoxyphenylmethanol

To a solution of3-benzyloxy-4-formyl-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole (0.14g) in tetrahydrofuran (1.8 mL) was added a solution of4-methoxyphenylmagnesium bromide in tetrahydrofuran (0.5 mol/L, 0.96 mL)at room temperature and the mixture was stirred at room temperature for1 hour. A small amount of water was added to the reaction mixture andthe mixture was purified by column chromatography on aminopropylatedsilica gel (eluent: tetrahydrofuran). Further purification by columnchromatography on silica gel (eluent: hexane/ethyl acetate=10/1-2/1)gave the title compound (0.11 g).

Process 5

1-Isopropyl-5-(4-methoxyphenyl)-4-[(4-methoxyphenyl)-methyl]-1,2-dihydro-3H-pyrazole-3-on

To a solution of[3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl]4-methoxy-phenylmethanol (0.11 g) in ethanol (4 mL) was added a catalytic amount of 10%palladium-carbon powder and the mixture was stirred at room temperatureunder a hydrogen atmosphere overnight. Dichloromethane was added to themixture and the insoluble material was removed by filtration. Thesolvent of filtrate was removed under reduced pressure to give the titlecompound (0.076 g).

¹H-NMR (CDCl₃) δ ppm:

1.36 (6H, d, J=6.6 Hz), 3.55 (2H, s), 3.75 (3H, s), 3.85 (3H, s),4.10-4.25 (1H, m), 6.70-6.80 (2H, m), 6.90-7.00 (2H, m), 7.05-7.20 (5H,m)

Process 6

3-(β-D-Glucopyranosyloxy)-1-isopropyl-5-(4-methoxyphenyl)-4-[(4-methoxyphenyl)methyl-1H-pyrazole

To a suspension of1-isopropyl-5-(4-methoxyphenyl)-4-[(4-methoxyphenyl)methyl]-1,2-dihydro-3H-pyrazole-3-one(0.066 g), acetobromo-α-D-glucose (0.39 g) andbenzyl-(n-tributyl)ammonium bromide (0.033 g) in dichloromethane (4 mL)was added sodium hydroxide (5 mol/L, 0.37 mL) and the mixture wasstirred at room temperature for 1.5 hours. The reaction mixture waspurified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran). The obtained semi purified1-isopropyl-5-(4-methoxyphenyl)-4-[(4-methoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acethyl-β-D-glucopyranosyloxy)-1H-pyrazolewas dissolved in methanol (3 mL) and sodium methoxide (28% methanolsolution, 0.36 mL) was added to the solution and the mixture was stirredat room temperature for 2 hours. The solvent of the reaction mixture wasremoved and methanol (0.5 mL), water (2 mL) and 10% citric acid solution(3 mL) were added to the residue. The mixture was purified by solidphase extraction on ODS (washing solvent: water, eluent: methanol).Preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18UG80, 5 μM, 20×50 mm, flow rate 30 mL/min linear gradient,water/methanol=90/10-10/90) was used for further purification to givethe title compound (0.047 g).

¹H-NMR (CD₃OD) δ ppm:

1.32 (3H, d, J=7.8 Hz), 1.33 (3H, d, J=6.5 Hz), 3.25-3.50 (4H, m), 3.56(1H, d, J=15.9 Hz), 3.61 (1H, d, J=15.9 Hz), 3.65-3.75 (1H, m), 3.71(3H, s), 3.75-3.86 (1H, m), 3.82 (3H, s), 4.15-4.35 (1H, m), 5.10-5.25(1H, m), 6.65-6.75 (2H, m), 6.90-7.00 (4H, m), 7.05-7.15 (2H, m)

EXAMPLES 2-74

The compounds described in Tables 1-14 were prepared in a similar mannerto that described in Example 1 using corresponding starting materialsand optionally by introducing a protective group. TABLE 1 ExampleChemical number structure ¹H-NMR (CD₃OD) δ ppm: Example 2

1.32 (3H, d, J=6.7 Hz), 1.34 (3H, d, J=6.5 Hz), 3.25-3.50 (4H, m),3.60-3.75 (3H, m), 3.82 (1H, dd, J=2.5. 12.0 Hz), 4.20-4.30 (1H, m),5.15-5.25 (1H, m), 6.95-7.25 (7H, m), 7.35-7.50 (3H, m) Example 3

1.33 (3H, d, J=6.7 Hz), 1.34 (3H, d, J=6.7 Hz), 3.30-3.50 (4H, m), 3.56(1H, d, J=15.7 Hz), 3.62 (1H, d, J=15.7 Hz), 3.69 (1H, dd, J=5.7, 12.2Hz), 3.71 (3H, s), 3.82 (1H, dd, J=2.2, 12.2 Hz), 4.20-4.30 (1H, m),5.15-5.25 (1H, m), 6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.15-7.25 (2H,m), 7.40-7.50 (3H, m) Example 4

1.34 (9H, s), 3.25-3.55 (6H, m), 3.69 (1H, dd, J=5.6, 12.1 Hz), 3.83(1H, dd, J=2.3, 12.1 Hz), 5.25-5.35 (1H, m), 6.90-7.00 (2H, m),7.00-7.20 (5H, m), 7.30-7.45 (3H, m) Example 5

1.34 (9H, s), 3.25-3.50 (6H, m), 3.65-3.75 (1H, m), 3.71 (3H, s), (1H,dd, J=2.3, 12.1 Hz), 5.20-5.35 (1H, m), 6.60-6.70 (2H, m), 6.80-6.90(2H, m), 7.10-7.20 (2H, m), 7.30-7.45 (3H, m) Example 6

3.30-3.50 (4H, m), 3.67 (1H, d, J=15.6 Hz), 3.70 (1H, dd, J=5.2, 12.0Hz), 3.73 (3H, s), 3.76 (1H, d, J=15.6 Hz), 3.87 (1H, dd, J=1.9, 12.0Hz), 5.35-5.45 (1H, m), 6.70-6.80 (2H, m), 7.00-7.15 (4H, m), 7.15-7.40(8H, m)

TABLE 2 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example7

3.30-3.55 (4H, m), 3.60-3.80 (6H, m), 3.80-3.95 (1H, m), 5.35-5.45 (1H,m), 6.70-6.80 (2H, m), 6.95-7.40 (11H, m) Example 8

1.34 (9H, s), 3.25-3.50 (6H, m), 3.65-3.75 (1H, m), 3.71 (3H, s), 3.83(1H, dd, J=2.3, 12.1 Hz), 5.20-5.35 (1H, m), 6.60-6.70 (2H, m),6.80-6.90 (2H, m), 7.10-7.20 (2H, m), 7.30-7.45 (3H, m) Example 9

1.45-1.65 (2H, m), 1.80-2.10 (6H, m), 3.30-3.50 (4H, m), 3.56 (1H, d,J=15.6 Hz), 3.61 (1H, d, J=15.6 Hz), 3.65-3.72 (1H, m), 3.71 (3H, s),4.30-4.45 (1H, m), 5.20-5.30 (1H, m), 6.65-6.75 (2H, m), 6.90-7.00 (2H,m), 7.15-7.25 (2H, m), 7.35-7.50 (3H, m) Example 10

3.20-3.55 (4H, m), 3.69 (1H, dd, J=5.3, 11.9 Hz), 3.73 (1H, d, J=15.8Hz), 3.83 (1H, d, J=15.8 Hz), 3.87 (1H, dd, J=1.7, 11.9 Hz), 5.35-5.45(1H, m), 7.00-7.40 (15H, m) Example 11

3.30-3.50 (4H, m), 3.69, (1H, dd, J=4.9, 12.0 Hz), 3.73 (1H, d, J=15.7Hz), 3.82 (1H, d, J=15.7 Hz), 3.87 (1H, dd, J=1.9, 12.0 Hz), 5.35-5.45(1H, m), 6.95-7.05 (2H, m), 7.05-7.15 (5H, m), 7.15-7.25 (4H, m),7.25-7.40 (3H, m) Example 12

1.45-1.60 (2H, m), 1.80-2.10 (6H, m), 3.30-3.50 (4H, m), 3.63 (1H, d,J=15.5 Hz), 3.68 (1H, d, J=15.5 Hz), 3.69 (1H, dd, J=5.3, 12.2 Hz), 3.82(1H, dd, J=2.5, 12.2 Hz), 4.30-4.45 (1H, m), 5.20-5.30 (1H, m),7.00-7.10 (3H, m), 7.10-7.25 (4H, m), 7.35-7.50 (3H, m)

TABLE 3 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example13

1.30-1.40 (6H, m), 3.25-3.50 (4H, m), 3.50-3.75(3H, m), 3.75-3.90 (1H,m), 4.15-4.30 (1H, m), 5.15-5.30 (1H, m), 6.95-7.25 (9H, m) Example 14

1.34 (3H, d, J=6.8 Hz), 1.34 (3H, d, J=6.7 Hz), 3.25-3.50 (4H, m),3.60-3.75 (3H, m), 3.83 (1H, dd, J=2.6, 12.0 Hz), 4.15-4.35 (1H, m),5.15-5.30 (1H, m), 6.80-7.25 (8H, m), 7.35-7.50 (1H, m) Example 15

1.20-1.40 (6H, m), 3.25-3.50 (4H, m), 3.50-3.75 (6H, m), 3.75-3.90 (1H,m), 3.95-4.10 (1H, m), 5.10-5.20 (1H, m), 6.90-7.15 (8H, m), 7.35-7.45(1H, m) Example 16

1.33 (3H, d, J=6.5 Hz), 1.34 (3H, d, J=6.7 Hz), 3.25-3.50 (4H, m),3.55-3.75 (6H, m), 3.82 (1H, dd, J=2.6, 12.2 Hz), 4.20-4.35 (1H, m),5.15-5.30 (1H, m), 6.60-6.70 (1H, m), 6.70-6.80 (1H, m), 6.90-7.00 (1H,m), 7.00-7.10 (3H, m), 7.10-7.20 (2H, m), 7.25-7.40 (1H, m) Example 17

1.32 (3H, d, J=6.6 Hz), 1.33 (3H, d, J=6.5 Hz), 3.25-3.50 (4H, m),3.55-3.75 (3H, m), 3.75-3.90 (4H, m), 4.20-4.30 (1H, m), 5.15-5.25 (1H,m), 6.90-7.20 (9H, m) Example 18

1.32 (3H, d, J=6.5 Hz), 1.33 (3H, d, J=6.7 Hz), 3.25-3.50 (4H, m), 3.56(1H, d, J=15.8 Hz), 3.61 (1H, d, J=15.8 Hz), 3.65-3.75 (1H, m), 3.71(3H, s), 3.82 (1H, dd, J=2.5, 12.0 Hz), 4.15-4.30 (1H, m), 5.15-5.25(1H, m), 6.65-6.75 (2H, m), 6.90-6.95 (2H, m), 7.10-7.25 (4H, m)

TABLE 4 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example19

1.33 (3H, d, J=6.6 Hz), 1.34 (3H, d, J=6.7 Hz), 3.30-3.50 (4H, m), 3.58(1H, d, J=15.7 Hz), 3.63 (1H, d, J=15.7 Hz), 3.65-3.75 (4H, m),4.15-4.30 (1H, m), 5.15-5.30 (1H, m), 6.60-6.80 (2H, m), 6.80-7.10 (4H,m), 7.10-7.20 (1H, m), 7.40-7.50 (1H, m) Example 20

1.20-1.40 (6H, m), 3.20-3.60 (6H, m), 3.60-3.75 (7H, m), 3.80-3.90 (1H,m), 3.95-4.10 (1H, m), 5.10-5.20 (1H, m), 6.60-6.70 (2H, m), 6.85-7.10(5H, m), 7.35-7.45 (1H, m) Example 21

1.33 (3H, d, J=6.6 Hz), 1.34 (3H, d, J=6.4 Hz), 3.25-3.50 (4H, m), 3.57(1H, d, J=15.7 Hz), 3.62 (1H, d, J=15.7 Hz), 3.65-3.75 (7H, m), 3.83(1H, dd, J=2.2, 12.1 Hz), 4.20-4.35 (1H, m), 5.15-5.25 (1H, m),6.60-6.80 (4H, m), 6.90-7.00 (3H, m), 7.30-7.40 (1H, m) Example 22

1.30-1.40 (6H, m), 3.20-3.30 (1H, m), 3.30-3.45 (3H, m), 3.55-3.75 (7H,m), 3.79 (1H, dd, J=2.4, 12.0 Hz), 4.20-4.35 (1H, m), 5.10-5.25 (1H, m),6.70-6.85 (2H, m), 6.90-7.00 (1H, m), 7.00-7.12 (1H, m), 7.13-7.25 (2H,m), 7.35-7.45 (3H, m) Example 23

1.33 (3H, d, J=6.9 Hz), 1.34 (3H, d, J=6.5 Hz), 3.25-3.55 (4H, m),3.55-3.75 (3H, m), 3.68 (3H, s), 3.82 (1H, dd, J=2.2, 12.0 Hz),4.15-4.35 (1H, m), 5.20-5.30 (1H, m), 6.55-6.70 (3H, m), 7.00-7.10 (1H,m), 7.15-7.25 (2H, m), 7.35-7.50 (3H, m) Example 24

3.20-3.55 (4H, m), 3.55-3.85 (4H, m), 3.88 (1H, dd, J=2.0, 12.0 Hz),5.40-5.50 (1H, m), 6.80-7.50 (14H, m)

TABLE 6 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example25

3.30-3.50 (4H, m), 3.69 (1H, dd, J=4.8, 12.0 Hz), 3.77 (1H, d, J=15.8Hz), 3.86 (1H, dd, J=1.8, 12.0 Hz), 3.87 (1H, d, J=15.8 Hz), 5.30-3.40(1H, m), 7.00-7.50 (14H, m) Example 26

3.30-3.55 (4H, m), 3.65 (1H, d, J=15.4 Hz), 3.70 (1H, dd, J=5.4, 12.0Hz), 3.73 (1H, d, J=15.4 Hz), 3.88 (1H, dd, J=2.2, 12.0 Hz), 5.40-5.50(1H, m), 6.70-6.80 (2H, m), 6.90-7.05 (5H, m), 7.05-7.15 (2H, m),7.15-7.30 (1H, m), 7.30-7.45 (3H, m) Example 27

3.30-3.55 (4H, m), 3.55-3.95 (7H, m), 5.30-5.40 (1H, m), 6.70-6.85 (2H,m), 7.00-7.55 (11H, m) Example 28

1.55-1.85 (2H, m), 2.05-2.25 (2H, m), 2.55-2.75 (2H, m), 3.30-3.50 (4H,m), 3.50-3.75 (6H, m ), 3.85 (1H, dd, J=1.9, 12.2 Hz), 4.45-4.60 (1H,m), 5.25-5.35 (1H, m), 6.65-6.80 (2H, m), 6.90-7.00 (2H, m), 7.10-7.2(2H, m), 7.35-7.50 (3H, m) Example 29

1.30-1.40 (6H, m), 3.20-3.45 (4H, m), 3.45-3.60 (2H, m), 3.62 (3H, s),3.68 (1H, dd, J=5.1, 12.2 Hz), 3.72 (3H, s), 3.80 (1H, dd J=2.3, 12.2Hz), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.30-6.40 (2H, m), 6.80-6.90(1H, m), 7.10-7.25 (2H, m), 7.35-7.45 (3H, m) Example 30

1.15-1.40 (6H, m), 3.25-3.50 (5H, m), 3.65-3.90 (4H, m), 5.15-5.35 (1H,m), 6.85-6.95 (2H, m), 6.95-7.10 (4H, m), 7.45-7.70 (2H, m), 7.75-7.85(1H, m) Example 31

1.34 (3H, d, J=6.5 Hz). 1.35 (3H, d, J=6.7 Hz), 3.30-3.55 (4H, m), 3.63(1H, d, J=15.8 Hz), 3.71 (1H, dd, J=5.4, 12.1 Hz), 3.84 (1H, dd, J=2.3,12.1 Hz), 4.10-4.25 (1H, m), 5.25-5.35 (1H, m), 6.95-7.20 (5H, m),7.30-7.40 (1H, m), 7.40-7.50 (1H, m), 7.55-7.65 (1H, m), 7.65-7.55 (1H,m)

TABLE 6 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example32

1.34 (3H, d, J=6.5 Hz), 1.35 (3H, d, J=6.4 Hz), 3.25-3.50 (4H, m),3.60-3.75 (3H, m), 3.83 (1H, dd, J=2.5, 12.0 Hz), 4.10-4.30 (1H, m),5.20-5.30 (1H, m), 6.95-7.20 (5H, m), 7.30-7.45 (2H, m), 7.65-7.75 (2H,m) Example 33

1.20-1.45 (6H, m), 3.25-3.50 (4H, m), 3.50-3.90 (4H, m), 4.00-4.15 (1H,m), 5.15-5.30 (1H, m), 6.90-7.30 (8H, m), 7.40-4.55 (1H, m) Example 34

1.15-1.40 (6H, m), 1.80-1.90 (3H, m), 3.30-3.5 (6H, m), 3.65-3.80 (1H,m), 3.80-3.95 (2H, m), 5.20-5.30 (1H, m), 6.88-6.96 (2H, m), 6.98-7.12(4H, m), 7.16-7.28 (2H, m), 7.30-7.38 (1H, m) Example 35

1.32 (3H, d, J=6.6 Hz), 1.33 (3H, d, J=6.5 Hz), 2.31 (3H, s), 3.25-3.50(4H, m), 3.55-3.75 (3H, m), 3.83 (1H, dd, J=2.2, 11.9 Hz), 4.20-4.30(1H, m), 5.15-5.2 (1H, m), 6.90-6.95 (1H, m), 6.95-7.00 (1H, m),7.00-7.10 (3H, m), 7.10-7.20 (2H, m), 7.20-7.35 (2H, m) Example 36

1.32 (3H, d, J=6.7 Hz), 1.33 (3H, d, J=6.8 Hz), 2.38 (3H, s), 3.25-3.50(4H, m), 3.55-3.75 (3H, m), 3.82 (1H, dd, J=2.2, 12.1 Hz), 4.20-4.35(1H, m), 5.15-5.25 (1H, m), 6.95-7.20 (7H, m), 7.20-7.30 (2H, m) Example37

1.15-1.40 (6H, m), 3.20-3.50 (5H, m), 3.60-3.90 (7H, m), 5.15-5.35 (1H,m), 6.55-6.70 (2H, m), 6.75-6.90 (2H, m), 7.00-7.10 (1H, m), 7.50-7.70(2H, m), 7.75-7.85 (1H, m)

TABLE 7 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example38

1.34 (3H, d, J=6.6 Hz), 1.35 (3H, d, J=6.7 Hz), 3.25-3.50 (4H, m), 3.57(1H, d, J=15.7 Hz), 3.62 (1H, d, J=15.7 Hz), 3.65-3.75 (4H, m), 3.85(1H, dd, J=2.3, 12.1 Hz), 4.10-4.25 (1H, m), 5.20-5.35 (1H, m),6.60-6.80 (2H, m), 6.85-7.00 (2H, m), 7.30-7.50 (2H, m), 7.55-7.80 (2H,m) Example 39

1.34 (3H, d, J=6.4 Hz), 1.35 (3H, d, J=6.8 Hz), 3.25-3.50 (4H, m), 3.59(1H, d, J=15.7 Hz), 3.64 (1H, d, J=15.7 Hz), 3.65-3.75 (4H, m),4.15-4.30 (1H, m), 5.20-5.30 (1H, m), 6.60-6.80 (2H, m), 6.85-7.00 (2H,m), 7.30-7.45 (2H, m), 7.65-7.80 (2H, m) Example 40

1.20-1.40 (6H, m), 3.25-3.75 (10H, m), 3.80-3.90 (1H, m), 4.00-4.15 (1H,m), 5.15-5.30 (1H, m), 6.60-6.70 (2H, m), 6.85-6.95 (2H, m), 7.05-7.25(3H, m), 7.40-7.55 (1H, m) Example 41

1.15-1.40 (6H, m), 1.85-1.95 (3H, m), 3.30-3.60 (6H, m), 3.60-3.80 (4H,m), 3.80-4.00 (2H, m), 5.20-5.30 (1H, m), 6.60-6.70 (2H, m), 6.80-6.90(2H, m), 6.95-7.10 (1H, m), 7.15-7.40 (3H, m) Example 42

1.32 (3H, d, J=6.3 Hz), 1.33 (3H, d, J=6.7 Hz), 2.32 (3H, s), 3.30-3.50(4H, m), 3.55 (1H, d, J=15.8 Hz), 3.60 (1H, d, J=15.8 Hz), 3.65-3.75(4H, m), 3.83 (1H, dd, J=2.3, 12.4 Hz), 4.15-4.30 (1H, m), 5.15-5.25(1H, m), 6.65-6.75 (2H, m), 6.90-7.05 (4H, m), 7.20-7.35 (2H, m) Example43

1.31 (3H, d, J=6.5 Hz), 1.32 (3H, d, J=6.7 Hz), 2.38 (3H, s), 3.25-3.50(4H, m), 3.56 (1H, d, J=15.5 Hz), 3.61 (1H, d, J=15.5 Hz), 3.65-3.75(4H, m), 4.15-4.35 (1H, m), 5.10-5.25 (1H, m), 6.65-6.75 (2H, m),6.90-7.00 (2H, m), 7.00-7.15 (2H, m), 7.15-7.30 (2H, m)

TABLE 8 Example Chemical number structure ¹H-MMR (CD₃OD) δ ppm: Example44

0.72 (3H, t, J=7.5 Hz), 1.60-1.75 (2H, m), 3.30-3.50 (4H, m), 3.56 (1H,d, J=15.8 Hz), 3.63 (1H, d, J=15.8 Hz), 3.60-2.74 (1H, m), 3.71 (3H, s),5.15-5.25 (1H, m), 6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.15-7.25 (2H,m), 7.40-7.50 (3H, m) Example 45

1.32 (3H, d, J=6.3 Hz), 1.33 (3H, d, J=6.2 Hz), 1.35-1.45 (3H, m),3.20-3.55 (4H, m), 3.56 (1H, d, J=15.8 Hz), 3.61 (1H, d, J=15.8 Hz),3.65-3.75 (4H, m), 4.00-4.15 (2H, m), 4.15-4.35 (1H, m), 5.10-5.25 (1H,m), 6.65-6.75 (2H, m), 6.90-7.00 (4H, m), 7.05-7.15 (2H, m) Example 46

1.25-1.40 (12H, m), 3.20-3.50 (4H, m), 3.56 (1H, d, J=15.6 Hz), 3.61(1H, d, J=15.6 Hz), 3.75-3.85 (1H, m), 4.20-4.35 (1H, m), 4.55-4.70 (1H,m), 5.10-5.25 (1H, m), 6.65-6.75 (2H, m), 6.85-7.00 (4H, m), 7.00-7.15(2H, m) Example 47

1.32 (3H, d, J=6.7 Hz), 1.33 (3H, d, J=6.2 Hz), 3.20-3.55 (4H, m),3.55-3.75 (3H, m), 3.81 (1H, dd, J=2.1, 12.0 Hz), 4.20-4.35 (1H, m),5.10-5.25 (1H, m), 6.75-6.85 (2H, m), 6.95-7.10 (5H, m), 7.10-7.20 (2H,m) Example 48

1.00 (3H, t, J=7.4 Hz), 1.25-1.40 (6H, m), 1.45-1.60 (2H, m), 1.70-1.85(2H, m), 3.20-3.47 (4H, m), 3.52-3.64 (2H, m), 3.68 (1H, dd, J=5.4 Hz,12.0 Hz), 3.71 (3H, s), 3.82 (1H, dd, J=2.3 Hz, 12.0 Hz), 4.01 (2H, t,J=6.6 Hz), 4.15-4.35 (1H, m), 5.18 (1H, d, J=7.3 Hz), 6.71 (2H, d, J=9.0Hz), 6.85-7.05 (4H, d, m), 7.08 (2H, d, J=9.0 Hz)

TABLE 9 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example49

0.90-1.03 (6H, m), 1.25-1.40 (6H, m), 1.60-1.79 (4H, m), 3.20-3.48 (4H,m), 3.52-3.65 (2H, m), 3.69 (1H, dd, J=5.4 Hz, 12.1 Hz), 3.71 (3H, s),3.82 (1H, dd, J=2.1 Hz, 12.1 Hz), 4.15-4.35 (2H, m), 5.17 (1H, d, J=7.1Hz), 6.70 (2H, d, J=8.8 Hz), 6.85-7.00 (4H, d, m), 7.07 (2H, d, J=8.8Hz), Example 50

1.32 (3H, d, J=6.7 Hz), 1.33 (3H, d, J=6.3 Hz), 1.55-2.05 (8H, m),3.25-3.50 (5H, m), 3.56 (1H, d, J=15.7 Hz), 3.61 (1H, d, J=15.7 Hz),3.69 (1H, dd, J=5.5, 12.0 Hz), 3.71 (3H, s), 3.82 (1H, dd, J=2.5, 12.0Hz), 4.20-4.35 (1H, m), 5.15-5.20 (1H, m), 6.65-6.75 (2H, m), 6.85-7.00(4H, m), 7.00-7.15 (2H, m) Example 51

1.30-1.35 (12H, m), 3.25-3.50 (4H, m), 3.60-3.75 (3H, m), 3.75-3.85 (1H,m), 4.20-4.35 (1H, m), 4.55-4.70 (1H, m), 5.15-5.20 (1H, m), 6.90-7.00(2H, m), 7.00-7.10 (5H, m), 7.10-7.20 (2H, m) Example 52

1.25-1.35 (12H, m), 3.25-3.50 (4H, m), 3.55-3.75 (3H, m), 3.83 (1H, dd,J=2.1, 12.0 Hz), 4.20-4.30 (1H, m), 4.55-4.70 (1H, m), 5.15-5.25 (1H,m), 6.80-6.90 (2H, m), 6.90-6.98 (2H, m), 6.99-7.10 (4H, m) Example 53

1.23 (3H, q, J=7.2 Hz), 3.30-3.50 (4H, m), 3.56 (1H, d, J=15.6 Hz), 3.63(1H, d, J=15.6 Hz), 3.65-3.75 (4H, m), 3.80-3.95 (3H, m), 5.15-5.25 (1H,m), 6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.15-5.25 (2H, m), 7.40-7.50(3H, m)

TABLE 10 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example54

0.69 (3H, d, J=6.6 Hz), 0.71 (3H, d, J=6.9 Hz), 1.90-2.10 (1H, m),3.25-3.50 (4H, m), 3.58 (1H, d, J=15.7 Hz), 3.63 (1H, d, J=15.7 Hz),3.65-3.75 (6H, m), 3.84 (1H, dd, J=2.1, 12.1 Hz), 5.15-5.25 (1H, m),6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.15-7.25 (2H, m), 7.35-7.45 (3H,m) Example 55

1.30-1.35 (6H, m), 3.20-3.50 (4H, m), 3.61 (1H, d, J=15.6 Hz), 3.66 (1H,d, J=15.6 Hz), 3.70 (1H, dd, J=5.4, 12.0 Hz), 3.84 (1H, dd, J=2.2, 12.0Hz), 4.15-4.25 (1H, m), 5.20-5.30 (1H, m), 6.80-6.90 (2H, m), 6.95-7.05(2H, m), 7.10-7.25 (4H, m) Example 56

0.93 (6H, d, J=6.6 Hz), 1.32 (3H, d, J=6.7 Hz), 1.33 (3H, d, J=6.4 Hz),1.80-1.95 (1H, m), 2.53 (2H, d, J=7.3 Hz), 3.25-3.50 (4H, m), 3.57 (1H,d, J=15.8 Hz), 3.62 (1H, d, J=15.8 Hz), 3.65-3.75 (4H, m), 3.83 (1H, dd,J=2.0, 11.9 Hz), 4.20-4.30 (1H, m), 5.15-5.25 (1H, m), 6.60-6.75 (2H,m), 6.85-6.95 (2H, m), 7.05-7.15 (2H, m), 7.15-7.25 (2H, m) Example 57

0.85-0.95 (3H, m), 1.20-1.45 (10H, m), 1.55-1.75 (2H, m), 2.60-2.70 (2H,m), 3.25-3.50 (4H, m), 3.56 (1H, d, J=15.7 Hz), 3.61 (1H, d, J=15.7 Hz),3.65-3.75 (4H, m), 3.82 (1H, dd, J=2.4, 12.0 Hz), 4.15-4.35 (1H, m),5.15-5.25 (1H, m), 6.65-6.75 (2H, m), 6.85-7.00 (2H, m), 7.05-7.15 (2H,m), 7.20-7.30 (2H, m) Example 58

0.96 (3H, t, J=7.5 Hz), 1.32 (3H, d, J=6.7 Hz), 1.33 (3H, d, J=6.8 Hz),1.30-1.45 (2H, m), 1.55-1.70 (2H, m), 2.60-2.70 (2H, m), 3.25-3.50 (4H,m), 3.56 (1H, d, J=15.7 Hz), 3.61 (1H, d, J=15.7 Hz), 3.65-3.75 (4H, m),3.82(1H, dd, J=2.3, 12.9 Hz), 4.20-4.35 (1H, m), 5.15-5.25 (1H, m),6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.05-7.15 (2H, m), 7.20-7.30 (2H,m)

TABLE 11 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example59

0.96 (3H, t, J=7.4Hz), 1.32 (3H, d, J=6.5Hz), 1.33 (3H, d, J=6.6Hz),1.60-1.75 (2H, m), 2.60-2.70 (2H, m), 3.25-3.50 (4H, m), 3.56 (1H, d,J=15.6Hz), 3.61 (1H, d, J=15.6Hz), 3.65-3.75 (4H, m), 3.75-3.90 (1H, m),4.20-4.30 (1H, m), 5.15-5.25 (1H, m), 6.65-6.75 (2H, m), 6.85-7.00 (2H,m), 7.05-7.15 (2H, m), 7.20-7.30 (2H, m) Example 60

1.28 (6H, d, J=6.9Hz), 1.32 (3H, d, J=6.6Hz), 1.33 (3H, d, J=6.6Hz),2.85-3.05 (1H, m), 3.25-3.50 (4H, m), 3.56 (1H, d, J=15.7Hz), 3.61 (1H,d, J=15.7Hz), 3.69 (1H, dd, J=5.4, 12.0Hz), 3.71 (3H, s), 3.82 (1H, dd,J=2.3, 12.0Hz), 4.20-4.35 (1H, m), 5.15-5.25 (1H, m), 6.65-6.75 (2H, m),6.90-7.00 (2H, m), 7.05-7.15 (2H, m), 7.25-7.35 (2H, m) Example 61

1.26 (3H, t, J=7.6Hz), 1.32 (3H, d, J=6.3Hz), 1.33 (3H, d, J=6.6Hz),2.69 (2H, q, J=7.7Hz), 3.25-3.35 (1H, m), 3.35-3.50 (3H, m), 3.56 (1H,d, J=15.7Hz), 3.61 (1H, d, J=15.7Hz), 3.69 (1H, dd, J=5.4, 12.1Hz), 3.71(3H, s), 3.82 (1H, dd, J=2.2, 12.1Hz), 4.20-4.35 (1H, m), 5.15-5.25 (1H,m), 6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.05-7.15 (2H, m), 7.20-7.35(2H, m) Example 62

1.34 (3H, d, J=6.7Hz), 1.34 (3H, d, J=6.6Hz), 3.25-3.35 (1H, m),3.35-3.50 (3H, m), 3.57 (1H, d, J=15.8Hz), 3.62 (3H, s), 3.63 (1H, d,J=15.7Hz), 3.69 (1H, dd, J=2.7, 12.2Hz), 3.85 (3H, s), 4.25-4.40 (1H,m), 5.15-5.25 (1H, m), 6.55-6.65 (1H, m), 6.70-6.80 (3H, m), 6.90-7.05(3H, m) Example 63

1.20-1.30 (6H, m), 3.30-3.70 (9H, m), 3.70-3.80 (1H, m), 3.80-3.95 (2H,m), 5.25-5.35 (1H, m), 6.45-6.55 (2H, m), 6.65-6.75 (2H, m), 7.20-7.30(1H, m), 7.30-7.45 (2H, m), 7.45-7.55 (2H, m), 7.90-8.00 (2H, m)

TABLE 12 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example64

1.35 (3H, d, J=6.5Hz), 1.36 (3H, d, J=6.5Hz), 3.25-3.50 (4H, m), 3.61(1H, d, J=15.7Hz), 3.66 (1H, d, J=15.7Hz), 3.69 (3H, s), 3.71 (1H, dd,J=5.4, 12.1 Hz), 3.85 (1H, dd, J=2.5, 12.1Hz), 4.25-4.40 (1H, m),5.20-5.30 (1H, m), 6.65-6.70 (2H, m), 6.90-7.00 (2H, m), 7.25-7.30 (1H,m), 7.50-7.60 (3H, m), 7.60-7.65 (1H, m), 7.75-7.85 (1H, m), 7.85-7.95(2H, m) Example 65

1.32 (3H, d, J=6.7Hz), 1.33 (3H, d, J=6.7Hz), 3.30-3.50 (4H, m), 3.57(1H, d, J=15.8Hz), 3.62 (1H, d, J=15.8Hz), 3.69 (1H, dd, J=5.4, 11.9Hz),3.71 (3H, s), 3.83 (1H, dd, J=2.2, 11.9Hz), 3.90 (3H, s), 4.15-4.30 (1H,m), 5.15-5.25 (1H, m), 6.65-6.75 (2H, m), 6.85-6.90 (1H, m), 6.90-7.00(3H, m), 7.10-7.20 (1H, m) Example 66

1.35 (3H, d, J=6.5Hz), 1.36 (3H, d, J=6.2Hz), 3.30-3.50 (4H, m), 3.62(1H, d, J=16.2Hz), 3.67 (1H, d, J=16.2Hz), 3.65-3.75 (4H, m), 3.84 (1H,dd, J=2.7, 12.0Hz), 4.25-4.40 (1H, m), 5.20-5.30 (1H, m), 6.65-6.75 (2H,m), 6.95-7.05 (2H, m), 7.20-7.30 (2H, m), 7.30-7.40 (1H, m), 7.40-7.50(4H, m) Example 67

1.31 (3H, d, J=6.6Hz), 1.32 (3H, d, J=6.6Hz), 2.15 (3H, s), 3.25-3.50(4H, m), 3.55 (1H, d, J=15.5Hz), 3.60 (1H, dd, J=15.5Hz), 3.69 (1H, dd,J=5.4, 12.1 Hz), 3.71 (3H, s), 3.83 (1H, dd, J=2.3, 12.1 Hz), 3.85 (3H,s), 4.20-4.35 (1H, m), 5.10-5.25 (1H, m), 6.65-6.75 (2H, m), 6.85-6.90(1H, m), 6.90-7.05 (4H, m) Example 68

1.32 (6H, t, J=6.2Hz), 1.40 (3H, t, J=7.0Hz), 3.25-3.50 (4H, m), 3.60(1H, d, J=15.7Hz), 3.65 (1H, d, J=15.7Hz), 3.69 (1H, dd, J=5.4, 12.0Hz),3.83 (1H, dd, J=2.2, 12.0Hz), 4.07 (2H, q, J=7.0Hz), 4.15-4.30 (1H, m),5.15-5.25 (1H, m), 6.80-6.90 (2H, m), 6.90-7.00 (2H, m), 7.00-7.10 (4H,m)

TABLE 13 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example69

1.30-1.35 (6H, m), 3.25-3.50 (4H, m), 3.61 (1H, d, J=15.7Hz), 3.66 (1H,d, J=15.7Hz), 3.69 (1H, dd, J=5.3, 12.1Hz), 3.83 (1H, dd, J=2.2,12.1Hz), 4.15-4.30 (1H, m), 4.58 (2H, q, J=8.5Hz), 5.15-5.30 (1H, m),6.80-6.90 (2H, m), 7.00-7.06 (2H, m), 7.06 (2H, m), 7.06-7.12 (2H, m),7.13-7.20 (2H, m) Example 70

3.25-3.50 (4H, m), 3.57 (1H, d, J=15.7Hz), 3.63 (1H, d, J=15.7Hz),3.65-3.75 (4H, m), 3.85 (1H, dd, J=2.1, 12.1Hz), 4.45-4.60 (2H, m),5.32-5.38 (1H, m), 6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.15-7.30 (2H,m), 7.40-7.50 (3H, m) Example 71

1.32 (3H, d, J=6.3Hz), 1.33 (3H, d, J=6.6Hz), 3.25-3.50 (4H, m), 3.56(1H, d, J=15.9Hz), 3.61 (1H, d, J=15.9Hz), 3.65-3.75 (4H, m), 3.82 (1H,dd, J=2.2, 11.9Hz), 4.15-4.30 (1H, m), 4.58 (2H, q, J=8.5Hz), 5.15-5.25(1H, m), 6.65-6.75 (2H, m), 6.90-7.00 (2H, m), 7.00-7.10 (2H, m),7.10-7.20 (2H, m) Example 72

1.30-1.40 (6H, m), 3.25-3.50 (4H, m), 3.60 (1H, d, J=15.7Hz), 3.62 (1H,d, J=15.7Hz), 3.69 (1H, dd, J=5.4, 12.2Hz), 3.71 (3H, s), 3.82 (1H, dd,J=2.1, 12.2Hz), 4.25-4.35 (1H, m), 5.15-5.25 (1H, m), 6.60-6.67 (2H, m),6.68-6.75 (2H, m), 6.80-6.90 (1H, m), 6.90-7.00 (2H, m), 7.20-7.30 (1H,m) Example 73

1.20-2.30 (3H, m), 1.35-1.45 (3H, m), 3.20-3.90 (10H, m), 3.75-3.85 (1H,m), 4.05-4.20 (1H, m), 5.05-5.20 (1H, m), 6.60-7.40 (8H, m)

TABLE 14 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example74

1.15-1.30 (6H, m), 3.25-3.75 (10H, m), 3.75-3.85 (1H, m), 4.00-4.15 (1H,m), 4.75-5.20 (3H, m), 6.50-7.50 (13H, m)

EXAMPLE 75

Process 1

4-[(4-Methylthiophenyl)methyl]-5-phenyl-1,2-dihydro-3H-pyrazole-3-one

To a solution of methyltiobenzylalcohol (0.31 g) and triethylamine (0.20g) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride (0.23 g)and the mixture was stirred at room temperature for 1 hour and then theinsoluble material was removed by filtration. The obtainedtetrahydrofuran solution of methanesulfonic acid 4-(methylthio)benzylester was added to a suspension of sodium hydride (60%, 0.080 g) and3-oxo-3-phenylpropionic acid ethyl ester (0.38 g) in 1,2-dimethoxyethane(1 mL) and the mixture was stirred at 60° C. overnight. Hydrazinemonohydrate (0.60 g) was added to the reaction mixture and the reactionmixture was stirred at 60° C. for 6 hours. The solvent of the reactionmixture was removed, and water was added to the residue. The mixture wasstirred. After the mixture was left at rest, water was removed bydecantation and water was added to the residue again. The mixture wasstirred and then left at rest, and water was removed by decantation. Theresidue was dried under reduced pressure. Diethyl ether and hexane wereadded. The precipitated material was collected by filtration and washedwith water and hexane, and dried under reduced pressure to give thetitle compound (0.37 g).

¹H-NMR (DMSO-d₆) δ ppm:

2.41 (3H, s), 3.76 (2H, s), 7.05-7.50 (9H, m)

Process 2

3-(β-D-Glucopyranosyloxy)-4-[(4-methylthiophenyl)methyl]-1H-pyrazole

To a suspension of4-[(4-methylthiophenyl)methyl]-5-phenyl-1,2-dihydro-3H-pyrazole-3-one(0.087 g), acetobromo-α-D-glucose (0.62 g) andbenzyltri(n-butyl)ammonium bromide (0.054 g) in dichloromethane (3 mL)was added a sodium hydroxide aqueous solution (5 mol/L, 0.9 mL), and themixture was stirred at room temperature overnight. The reaction mixturewas purified by column chromatography on aminopropylated silica gel(eluent: tetrahydrofuran). The obtained semi purified4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetraacethyl-β-D-glucopyranosyloxy)-1H-pyrazolewas dissolved in methanol (5 mL), and sodium methoxide (28% methanolsolution, 0.28 mL) was added to the solution. The mixture was stirred atroom temperature for 2 hours. Acetic acid (0.090 g) was added to thereaction mixture, and the solvent was removed. Water (5 mL) was added tothe residue, and the mixture was purified by solid phase extraction onODS (washing solvent: water/methanol=5/1, eluent: methanol). Columnchromatography on silica gel (eluent: dichloromethane/methanol=20/1-7/1)was used for further purification to give the title compound (0.033 g).

¹H-NMR (CD₃OD) δ ppm:

3.30-3.45 (4H, m), 3.69 (1H, dd, J=4.7, 11.8 Hz), 3.80-3.95 (3H, m),5.15-5.25 (1H, m), 7.05-7.20 (4H, m), 7.30-7.45 (5H, m)

EXAMPLES 76-85

The compounds described in Tables 15-16 were prepared in a similarmanner to that described in Example 75 by using corresponding startingmaterials. TABLE 15 Example Chemical number structure ¹H-NMR (CD₃OD) δppm: Example 76

3.30-3.45 (4H, m), 3.60-3.75 (1H, m), 3.73 (3H, s), 3.78-3.95 (3H, m),5.10-5.30 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m), 7.30-7.45 (5H,m) Example 77

1.34 (3H, t, J=6.9Hz), 3.30-3.50 (4H, m), 3.65-3.75 (1H, m), 3.75-3.95(3H, m), 3.96 (2H, q, J=7.1Hz), 5.10-5.25 (1H, m), 6.70-6.80 (2H, m),7.00-7.15 (2H, m), 7.30-7.45 (5H, m) Example 78

1.01 (3H, t, J=7.4Hz), 1.65-1.80 (2H, m), 3.30-3.50 (4H, m), 3.65-3.75(1H, m), 3.75-3.95 (5H, m), 5.10-5.25 (1H, m), 6.70-6.80 (2H, m),7.00-7.15 (2H, m), 7.30-7.50 (5H, m) Example 79

1.20-1.30 (6H, m), 3.30-3.50 (4H, m), 3.65-3.75 (1H, m), 3.75-3.95 (3H,m), 4.45-4.55 (1H, m), 5.15-5.25 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10(2H, m), 7.30-7.50 (5H, m) Example 80

0.97 (3H, t, J=7.4Hz), 1.40-1.55 (2H, m), 1.65-1.80 (2H, m), 3.30-3.50(4H, m), 3.65-3.75 (1H, m), 3.75-3.95 (5H, m), 5.10-5.25 (1H, m),6.70-7.85 (2H, m), 7.0-7.15 (2H, m), 7.30-7.45 (5H, m) Example 81

1.18 (3H, t, J=7.6Hz), 2.57 (2H, q, J=7.5Hz), 3.30-3.45 (4H, m),3.65-3.75 (1H, m), 3.80-3.95 (3H, m), 5.15-5.25 (1H, m), 7.00-7.15 (4H,m), 7.30-7.45 (5H, m)

TABLE 16 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example82

0.90 (3H, t, J=7.3Hz), 1.50-1.65 (2H, m), 2.45-4.55 (2H, m), 3.30-3.50(4H, m), 3.65-3.75 (1H, m), 3.80-4.00 (3H, m), 5.10-5.25 (1H, m),7.00-7.15 (4H, m), 7.30-7.50 (5H, m) Example 83

1.15-1.25 (6H, m), 2.75-2.90 (1H, m), 3.30-3.45 (4H, m), 3.65-3.75 (1H,m), 3.80-4.00 (3H, m), 5.10-5.25 (1H, m), 7.00-7.20 (4H, m), 7.30-7.50(5H, m) Example 84

0.87 (6H, d, J=6.6Hz), 1.70-1.90 (1H, m), 2.40 (2H, d, J=7.4Hz),3.30-3.50 (4H, m), 3.65-3.75 (1H, m), 3.80-4.00 (3H, m), 5.15-5.25 (1H,m), 6.95-7.05 (2H, m), 7.05-7.10 (2H, m), 7.30-7.45 (5H, m) Example 85

3.30-3.50 (4H, m), 3.70 (1H, dd, J=4.9, 12.1Hz), 3.86 (1H, dd, J=1.8,12.1Hz), 1.93 (1H, d, J=16.4Hz), 4.01 (1H, d, J=16.4Hz), 5.15-5.30 (1H,m), 5.20-7.60 (14H, m)

EXAMPLE 86

4-Benzyl-5-(4-benzyloxyphenyl)-3-(β-D-glucopyranosyloxy)-1-isopropyl-1H-pyrazole

To a suspension of4-benzyl-3-(β-D-glucopyranosyloxy)-5-(4-hydroxyphenyl)-1-isopropyl-1H-pyrazole(0.02 g) and potassium carbonate (0.017 g) in N,N-dimethylformamide (20mL) was added benzyl bromide at room temperature. The reaction mixturewas stirred at 50° C. for 3 hours. After the reaction mixture wasacidified by adding a hydrochloric acid aqueous solution (1 mol/L), themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to givethe title compound.

¹H-NMR (CD₃OD) δ ppm:

1.32 (3H, d, J=6.4 Hz), 1.33 (3H, d, J=6.3 Hz), 3.20-3.50 (4H, m),3.55-3.75 (3H, m), 3.81 (1H, dd, J=2.5, 12.2 Hz), 4.20-4.35 (1H, m),5.10-5.15 (2H, m), 5.15-5.25 (1H, m), 6.95-7.20 (9H, m), 7.20-7.50 (5H,m)

EXAMPLE 87

Process 1

4-Methyl-3-oxothiopentanoic acid O-benzyl ester

To a suspension of sodium amide (3.9 g) in toluene (150 mL) was added amixture of dithiocarbonic acid O-benzyl ester S-methyl ester (9.9 g) and3-methyl-2-butanone (4.3 g) at room temperature and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto a hydrochloric acid aqueous solution (1 mol/L, 500 mL), and themixture was extracted with diethyl ether. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent:hexane—hexane/ethyl acetate=20/1)to give the title compound (4.6 g).

Process 2

3-Benzyloxy-1,5-diisopropyl-1H-pyrazole

To a suspension of 4-methyl-3-oxothiopentanoic acid O-benzyl ester (0.84g) and isopropylhydrazine hydrochloride (0.52 g) in acetonitrile (4 mL)was added triethylamine (1.4 g), and the mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture, and themixture was extracted with diethyl ether. The solvent of the organiclayer was removed under reduced pressure, and the residue was purifiedby column chromatography on silica gel (hexane/dichloromethane=1/1-2/3)to give the title compound (0.44 g).

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 1.43 (6H, d, J=6.6 Hz), 2.80-3.00 (1H, m),4.25-4.40 (1H, m), 5.14 (2H, s), 5.43 (1H, s), 7.25-7.40 (3H, m),7.40-7.50 (2H, m).

Process 3

3-Benzyloxy-4-formyl-1,5-diisopropyl-1H-pyrazole

To a solution of 3-benzyloxy-1,5-diisopropyl-1H-pyrazole (0.44 g) inN,N-dimethylformamide (3 mL) was added phosphorus oxychloride (0.31 g)at 80° C., and the mixture was stirred at 80° C. for 30 minutes. Afterthe reaction mixture was cooled to room temperature, a sodium hydroxideaqueous solution (1 mol/L) was added to the reaction mixture. Themixture was extracted with diethyl ether. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was removed underreduced pressure to give the title compound (0.42 g).

¹H-NMR (CDCl₃) δ ppm:

1.36 (6H, d, J=7.5 Hz), 1.45 (6H, d, J=6.5 Hz), 3.40-3.60 (1H, m),4.40-4.60 (1H, m), 5.30 (2H, s), 7.25-7.43 (3H, m), 7.44-7.52 (2H, m),9.82 (1H, s)

Process 4

4-Benzyl-1,5-diisopropyl-1,2-dihydro-3H-pyrazole-3-one

To a solution of 3-benzyloxy-4-formyl-1,5-diisopropyl-1H-pyrazole (0.21g) in tetrahydrofuran (10 mL) was added a solution of phenylmagnesiumbromide in tetrahydrofuran (1 mol/L, 1.5 mL) at room temperature, andthe mixture was stirred at room temperature for 2 hours. A saturatedammonium chloride aqueous solution and water were added to the reactionmixture, and the mixture was purified by column chromatography onaminopropylated silica gel (eluent:tetrahydrofuran). Furtherpurification by column chromatography on silica gel (eluent:hexane/ethylacetate=10/1-2/1) to give the adduct material,[3-benzyloxy-1,5-diisopropyl-1H-pyrazole-4-yl] phenyl methanol. Theobtained adduct material was dissolved in ethanol, and a catalyticamount of 10% palladium-carbon powder was added to the solution. Themixture was stirred at room temperature under a hydrogen atmosphereovernight. The insoluble material was removed by filtration, and thesolvent of the filtrate was removed under reduced pressure to give thetitle compound (0.16 g).

¹H-NMR (CDCl₃) δ ppm:

1.16 (6H, d, J=7.0 Hz), 1,41 (6H, d, J=6.7 Hz), 2.95-3.10 (1H, m), 3.77(2H, s), 4.25-4.45 (1H, m), 7.10-7.7.18 (1H, m), 7.20-7.30 (4H, m)

Process 5

4-Benzyl-3-(β-D-glucopyranosyloxy)-1,5-diisopropyl-1H-pyrazole

To a suspension of4-benzyl-1,5-diisopropyl-1,2-dihydro-3H-pyrazole-3-one (0.078 g),acetobromo-α-D-glucose (0.62 g) and benzyl(n-tributyl)ammonium bromide(0.054 g) in dichloromethane (4 mL) was added a sodium hydroxide aqueoussolution (5 mol/L, 0.6 mL) and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was purified by columnchromatography on aminopropylated silica gel (eluent:tetrahydrofuran).The obtained semi purified4-benzyl-3-1,5-diisopropyl-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazolewas dissolved in methanol (3 mL), and sodium methoxide (28% methanolsolution, 0.58 mL) was added to the solution. The mixture was stirred atroom temperature for 2 hours. The solvent of the reaction mixture wasremoved under reduced pressure, and the residue was acidified by adding10% citric acid aqueous solution. The mixture was purified by solidphase extraction on ODS (washing solvent:water, eluent:methanol).Further purification by column chromatography on silica gel(eluent:dichloromethane/methanol=10/1) gave the title compound (0.11 g).

¹H-NMR (CD₃OD) δ ppm:

1.10-1.20 (6H, m), 1.39 (3H, d, J=6.6 Hz), 1.40 (3H, d, J=6.8 Hz),3.05-3.15 (1H, m), 3.20-3.45 (4H, m), 3.65 (1H, dd, J=5.4, 12.1 Hz),3.77 (1H, dd, J=2.5, 12.1 Hz), 3.79 (1H, d, J=16.7 Hz), 3.85 (1H, d,J=16.7 Hz), 4.45-4.55 (1H, m), 5.05-5.15 (1H, m), 7.05-7.25 (5H, m)

EXAMPLES 88-101

The compounds described in Tables 17-19 were prepared in a similarmanner to that described in Example 87 using corresponding startingmaterials. TABLE 17 Example Chemical number structure ¹H-NMR (CD₃OD) δppm: Example 88

1.14 (3H, d, J=7.4Hz), 1.15 (3H, d, J=7.0Hz), 1.38 (3H, d, J=7.0Hz),1.40 (3H, d, J=6.8Hz), 3.05-3.15 (1H, m), 3.20-3.45 (4H, m), 3.66 (1H,dd, J=5.3, 11.9Hz), 3.68-3.90 (6H, m), 4.45-4.55 (1H, m), 5.05-5.15 (1H,m), 6.75-6.85 (2H, m), 7.00-7.10 (2H, m) Example 89

1.14 (3H, d, J=7.1Hz), 1.17 (3H, d, J=7.1Hz), 1.60 (9H, s), 3.20-3.45(4H, m), 3.45-3.60 (1H, m), 3.64 (1H, dd, J=5.2, 12.1Hz), 3.79 (1H, dd,J=2.0, 12.1Hz), 3.86 (1H, d, J=16.7Hz), 3.92 (1H, d, J=16.7Hz), 5.18(1H, d, J=7.6Hz), 7.05-7.25 (5H, m) Exampel 90

1.15 (3H, d, J=7.2Hz), 1.18 (3H, d, J=7.2Hz), 3.20-3.45 (4H, m),3.45-3.60 (1H, m), 3.65 (1H, dd, J=5.5, 12.0Hz), 3.73 (3H, s), 3.78 (1H,d, J=16.6Hz), 3.80 (1H, dd, J=2.2, 12.0Hz), 3.84 (1H, d, J=16.6Hz), 5.18(1H, d, J=7.1Hz), 6.75-6.80 (2H, m), 7.00-7.10 (2H, m)

TABLE 18 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example91

1.04 (3H, d, J=7.0Hz), 1.06 (3H, d, J=7.1Hz), 2.90-3.00 (1H, m),3.25-3.45 (4H, m), 3.66 (1H, dd, J=5.3, 11.9Hz), 3.83 (1H, dd, J=1.9,11.9Hz), 3.89 (1H, d, J=16.4Hz), 5.15-5.25 (1H, m), 7.10-7.20 (1H, m),7.20-7.30 (4H, m), 7.35-7.55 (5H, m) Example 92

1.05 (3H, d, J=7.1Hz), 1.07 (3H, d, J=7.9Hz), 2.90-3.00 (1H, m),3.25-3.50 (4H, m), 3.66 (1H, dd, J=5.3, 11.9Hz), 3.82 (1H, d, J=16.1Hz),3.83 (1H, dd, J=2.0, 11.9Hz), 3.90 (1H, d, J=16.1Hz), 5.15-5.25 (1H, m),6.75-6.85 (2H, m), 7.10-7.20 (2H, m), 7.30-7.55 (5H, m) Example 93

1.00-1.10 (6H, m), 2.80-3.00 (1H, m), 3.25-3.45 (4H, m), 3.66 (1H, dd,J=5.5, 11.9Hz), 3.75 (3H, s), 3.77-3.95 (3H, m), 5.15-5.30 (1H, m),6.75-6.85 (2H, m), 7.10-7.20 (2H, m), 7.20-7.30 (2H, m), 7.35-7.50 (2H,m) Example 94

1.36 (3H, d, J=6.9Hz), 1.39 (3H, d, J=6.3Hz), 1.65-1.80 (1H, m),1.85-2.05 (1H, m), 2.10-2.35 (4H, m), 3.15-3.45 (4H, m), 3.50-3.65 (1H,m), 3.64 (1H, dd, J=5.5, 12.1Hz), 3.75 (1H, dd, J=2.5Hz), 3.85 (1H, d,J=16.7Hz), 3.91 (1H, d, J=16.7Hz), 4.35-4.50 (1H, m), 5.00-5.10 (1H, m),7.05-7.30 (5H, m) Example 95

1.05-1.35 (3H, m), 1.38 (3H, d, J=6.4Hz), 1.39 (3H, d, J=6.9Hz),1.40-1.80 (7H, m), 2.60-2.80 (1H, m), 3.20-3.45 (4H, m), 3.65 (1H, dd,J=5.5, 12.1Hz), 3.78 (1H, dd, J=2.4, 12.1Hz), 3.80 (1H, d, J=16.3Hz),3.86 (1H, d, J=16.3Hz), 4.45-4.60 (1H, m), 5.05-5.15 (1H, m), 7.05-7.25(5H, m) Example 96

1.36 (3H, d, J=7.3Hz), 1.37 (3H, d, J=7.4Hz), 1.65-1.80 (1H, m),1.85-2.05 (1H, m), 2.10-2.35 (4H, m), .3.20-3.40 (4H, m), 3.50-3.65 (1H,m), 3.65 (1H, dd, J=5.4, 12.1Hz), 3.74 (3H, s), 3.76 (1H, dd, J=2.3,12.1Hz), 3.78 (1H, d, J=16.8Hz), 3.84 (1H, d, J=16.8Hz), 4.35-4.50 (1H,m), 5.00-5.10 (1H, m), 6.75-6.85 (2H, m), 7.00-7.10 (2H, m)

TABLE 19 Example Chemical number structure ¹HNMR (CD₃OD) δ ppm: Example97

1.05-1.35 (3H, m). 1.328 (3H, d, J=6.6Hz),1.39 (3H, d, J=7.1Hz),1.40-1.80 (7H, m), 2.65-2.80 (1H, m), 3.20-3.30 (1H, m), 3.30-3.45 (3H,m), 3.66 (1H, dd, J=5.5, 12.1), 3.70-3.85 (6H, m), 4.45-4.60 (1H, m),5.05-5.15 (1H, m), 6.75-6.85 (2H, m), 7.00-7.10 (2H, m) Example 98

1.05-1.15 (6H, m), 2.90-3.10 (1H, m), 3.25-3.45 (4H, m), 3.67 (1H, dd,J=5.3, 11.9Hz), 3.75 (3H, s), 3.74-3.95 (3H, m), 5.20-5.30 (1H, m),6.75-6.85 (2H, m), 7.10-7.30 (5H, m), 7.45-7.60 (1H, m) Example 99

0.95-1.10 (6H, m), 2.70-2.85 (1H, m), 3.30-3.45 (4H, m), 3.66 (1H, dd,5.0, 11.8Hz), 3.75 (3H, s), 3.76-3.95 (4H, m), 5.15-5.25 (1H, m),6.75-6.90 (2H, m), 7.10-7.20 (2H, m), 7.25-7.40 (2H, m), 7.40-7.60 (2H,m) Example 100

0.82 (3H, d, J=6.7Hz), 0.83 (3H, d, J=6.7Hz), 1.36 (3H, d, J=7.1Hz),1.37 (3H, d, J=6.7Hz), 1.60-1.80 (1H, m), 2.25-2.40 (2H, m), 3.25-3.45(4H, m), 3.67 (1H, dd, J=5.5, 12.0Hz), 3.70-3.85 (3H, m), 4.30-4.45 (1H,m), 5.05-5.15 (1H, m), 7.05-7.25 (5H, m) Example 101

0.83 (3H, d, J=6.6Hz), 0.83 (3H, d, J=6.6Hz), 1.35 (3H, d, J=6.7Hz),1.37 (3H, d, J=7.0Hz), 1.65-1.80 (1H, m), 2.34 (1H, d, J=7.6Hz),3.25-3.45 (4H, m), 3.60-3.75 (3H, m), 3.73 (3H, s), 3.80 (1H, dd, J=2.1,12.1Hz), 4.30-4.45 (1H, m), 5.00-5.15 (1H, m), 6.70-6.85 (2H, m),7.00-7.15 (2H, m)

EXAMPLE 102

Process 1

4-Isobutylbenzylalcohol

To a solution of 4-isobutylbenzaldehyde (2.4 g) in methanol (10 mL) wasadded sodium borohydride (0.85 g) at room temperature, and the mixturewas stirred at room temperature overnight. Water was added to thereaction mixture, and the mixture was extracted with diethyl ether. Theorganic layer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive the title compound (2.3 g).

¹H-NMR (CDCl₃) δ ppm:

0.90 (6H, d, J=6.6 Hz), 1.62 (1H, t, J=6.0 Hz), 1.75-1.95 (1H, m), 2.47(1H, d, J=7.0 Hz), 4.66 (1H, d, J=6.0 Hz), 7.10-7.20 (2H, m), 7.20-7.35(2H, m)

Process 2

4-[(4-Isobutylphenyl)methyl]-5-isopropyl-1,2-dihydro-3H-pyrazole-3-one

To a solution of 4-isobutylbenzylalcohol (0.33 g) and triethylamine(0.20 g) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride(0.23 g). After the mixture was stirred at room temperature for 1 hour,the insoluble material of the reaction mixture was removed byfiltration. The obtained solution of methanesulfonic acid4-isobutylbenzyl ester in tetrahydrofuran was added to a suspension ofsodium hydride (60%, 0.080 g) and 4-methyl-3-oxopentanoic acid methylester (0.29 g) in 1,2-dimethoxyethane (3 mL), and the mixture wasstirred at 60° C. overnight. Hydrazine monohydrate (0.60 g) was added tothe reaction mixture, and the mixture was stirred at 60° C. overnight.The solvent of the reaction mixture was removed under reduced pressure,and water was added to the residue. The mixture was stirred and thenleft at rest. Water was removed by decantation. Water was added to theresidue again, and the mixture was stirred and then left at rest. Waterwas removed by decantation. The residue was dried under reducedpressure, and diethyl ether and hexane were added to the residue. Theprecipitated material was collected by filtration, washed with water andthen hexane, and dried under reduced pressure to give the title compound(0.25 g).

¹H-NMR (DMSO-d₆) δ ppm:

0.82 (6H, d, J=6.6 Hz), 1.05 (6H, d, J=7.3 Hz), 1.70-1.85 (1H, m), 2.37(2H, d, J=7.0 Hz), 2.75-2.90 (1H, m), 3.53 (2H, s), 6.95-7.10 (4H, m)

Process 3

3-(β-D-Glucopyranosyloxy)-4-[(4-isobutyphenyl)methyl]-5-isopropyl-1H-pyrazole

To a suspension of4-[(4-isobutylphenyl)methyl]-5-isopropyl-1,2-dihydro-3H-pyrazole-3-one(0.082 g), acetobromo-α-D-glucose (0.62 g) andbenzyl(n-tributyl)ammonium bromide (0.054 g) in dichloromethane (3 mL)was added a sodium hydroxide aqueous solution (5 mol/L, 0.9 mL), and themixture was stirred at room temperature overnight. The reaction mixturewas purified by column chromatography on aminopropylated silica gel(eluent:tetrahydrofuran). The obtained semi purified5-isopropyl-4-[(4-isobutylphenyl)methyl]-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazolewas dissolved in methanol (5 mL), and sodium methoxide (28% methanolsolution, 0.29 mL) was added to the solution. The mixture was stirred atroom temperature for 2 hours. The solvent of the reaction mixture wasremoved under reduced pressure, and water was added to the residue. Themixture was purified by solid phase extraction (washing solvent:water,eluent:methanol). Further purification by column chromatography onsilica gel (eluent:dichloromethane/methanol=20/1-7/1) gave the titlecompound (0.080 g).

¹H-NMR (CD₃OD) δ ppm:

0.87 (6H, d, J=6.6 Hz), 1.10 (3H, d, J=7.3 Hz), 1.11 (3H, d, J=7.2 Hz),1.70-1.90 (1H, m), 2.41 (2H, d, J=7.0 Hz), 2.80-2.95 (1H, m), 3.30-3.45(4H, m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m), 5.00-5.15 (1H, m),6.95-7.05 (2H, m), 7.05-7.15 (2H, m)

EXAMPLES 103-118

The compounds described in Tables 20-22 were prepared in a similarmanner to that described in Example 102 using corresponding startingmaterials. TABLE 20 Example Chemical number structure ¹H-NNR (CD₃OD) δppm: Example 103

1.16 (3H, d, J=7.4Hz), 1.16 (3H, d, J=7.2Hz), 2.85-3.00 (1H, m),3.30-3.45 (4H, m), 3.68 (1H, dd, J=5.0, 12.0Hz), 3.75-3.90 (3H, m),5.05-5.15 (1H, m), 7.25-7.35 (3H, m), 7.35-7.45 (2H, m), 7.45-7.52 (2H,m), 7.5-7.60 (2H, m) Example 104

1.05 (3H, t. J=7.5Hz), 2.47 (2H, q, J=7.5Hz), 3.30-3.45 (4H, m),3.60-3.80 (6H, m), 3.80-3.90 (1H, m), 5.00-5.10 (1H, m), 6.75-6.85 (2H,m), 7.05-7.14 (2H, m) Example 105

0.82 (3H, t, J=7.3Hz), 1.40-1.55 (2H, m), 2.35-2.45 (2H, m), 3.30-3.45(4H, m), 3.60-3.80 (6H, m), 3.80-3.90 (1H, m), 5.00-5.10 (1H, m),6.75-6.85 (2H, m), 7.05-7.15 (2H, m) Example 106

1.12 (3H, d, J=7.4Hz), 1.13 (3H, d, J=7.2Hz), 2.80-2.95 (1H, m),3.30-3.45 (4H, m), 3.60-3.80 (6H, m), 3.80-3.90 (1H, m), 5.00-5.15 (1H,m), 6.75-7.85 (2H, m), 7.05-7.15 (2H, m) Example 107

2.09 (3H, s), 3.30-3.45 (4H, m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m),5.00-5.10 (1H, m), 6.80-6.90 (2H, m), 6.90-6.95 (2H, m), 7.00-7.10 (1H,m), 7.15-7.25 (2H, m), 7.25-7.35 (2H, m)

TABLE 21 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example108

2.04 (3H, s), 3.30-3.45 (4H, m), 3.60-3.75 (3H, m), 3.80-3.90 (1H, m),4.95-5.10 (3H, m), 6.80-6.90 (2H, m), 7.05-7.15 (2H, m), 7.20-7.50 (5H,m) Example 109

1.10-1.20 (6H, m), 2.58-3.00 (1H, m), 3.25-3.40 (4H, m), 3.60-3.70 (3H,m), 3.74 (3H, s), 3.80-3.90 (1H, m), 3.82 (3H, s), 5.00-5.10 (1H, m),6.37 (1H, dd, J=2.6, 8.1Hz), 6.47 (1H, d, J=2.6Hz), 6.89 (1H, d,J=8.1Hz) Exampel 110

1.02 (3H, t, J=7.6Hz), 1.12 (3H, d, J=7.1Hz), 1.13 (3H, d, J=7.4Hz),1.70-1.80 (2H, m), 2.80-3.00 (1H, m), 3.30-3.45 (4H, m), 3.66 (1H, d,J=16.1Hz), 3.67 (1H, dd, J=5.1, 12.1Hz), 3.73 (1H, d, J=16.1Hz), 3.84(1H, dd, J=1.8, 12.1Hz), 3.87 (2H, d, J=6.3Hz), 5.00-5.15 (1H, m),6.70-6.80 (2H, m), 7.05-7.15 (2H, m) Example 111

0.97 (3H, t, J=7.4Hz), 1.12 (3H, d, J=6.9Hz), 1.13 (3H, d, J=7.1Hz),1.40-1.55 (2H, m), 1.65-1.80 (2H, m), 2.80-3.00 (1H, m), 3.30-3.45 (4H,m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m), 3.91 (2H, t, J=6.4Hz),5.00-5.15 (1H, m), 6.70-6.80 (2H, m), 7.05-7.15 (2H, m) Example 112

1.11 (3H, d, J=7.2Hz), 1.12 (3H, d, J=7.4Hz), 2.26 (3H, s), 2.80-2.95(1H, m), 3.30-3.45 (4H, m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m),5.00-5.15 (1H, m), 7.0-7.10 (4H, m) Example 113

0.90 (3H, t, J=7.5Hz), 1.11 (3H, d, J=7.4Hz), 1.12 (3H, d, J=7.4Hz),1.50-1.65 (2H, m), 2.45-2.55 (2H, m), 2.80-2.95 (1H, m), 3.30-3.45 (4H,m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m), 5.00-5.15 (1H, m), 6.95-7.15(4H, m)

TABLE 22 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example114

1.12 (3H, d, J=7.9Hz), 1.13 (3H, d, J=6.7Hz), 1.20 (6H, d, J=7.0Hz),2.75-2.95 (2H, m), 3.30-3.45 (4H, m), 3.60-3.90 (4H, m), 5.00-5.15 (1H,m), 7.05-7.15 (4H, m) Example 115

1.13 (3H, d, J=7.2Hz), 1.13 (3H, d, J=7.1Hz), 2.42 (3H, s), 2.80-2.95(1H, m), 3.30-3.45 (4H, m), 3.67 (1H, dd, J=5.3, 12,2Hz), 3.70 (1H, d,J=15.8Hz), 3.76 (1H, d, J=15.8Hz), 3.84 (1H, dd, J=1.7, 12.2Hz),5.05-5.15 (1H, m), 7.15-7.20 (4H, m) Example 116

0.95-1.00 (6H, m), 1.65-1.75 (2H, m), 2.02 (3H, s), 3.25-3.40 (4H, m),3.55-3.70 (3H, m), 3.74 (3H, s), 4.00 (2H, d, J=6.6Hz), 4.95-5.10 (1H,m), 6.37 (1H, dd, J=2.5, 8.3Hz), 6.46 (1H, d, J=2.5Hz), 6.90 (1H, d,J=8.3Hz) Example 117

1.22 (9H, s), 3.25-3.45 (4H, m), 3.67 (1H, dd, J=5.1, 11.8Hz), 3.73 (3H,s), 3.75-3.95 (3H, m), 5.05-5.15 (1H, m), 6.75-6.80 (2H, m), 7.00-7.10(2H, m) Example 118

1.05-1.20 (6H, m), 2.80-3.00 (1H, m), 3.25-3.45 (4H, m), 3.50-3.75 (3Hm), 3.75-3.95 (7H, m), 3.95-4.05 (2H, m), 5.00-5.10 (1H, m), 6.35-6.45(1H, m), 6.50-6.60 (1H, m), 6.85-6.95 (1H, m)

EXAMPLE 119

Process 1

3-Benzyloxy-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-isopropyl-1H-pyrazole

To a solution of dithiocarbonic acid O-benzyl ester S-methyl ester (0.99g) and 1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)ethanone (0.89 g) in toluene(20 mL) was added sodium amide (0.39 g) at room temperature, and themixture was stirred at room temperature for 3 days. A hydrochloric acidaqueous solution (2 mol/L) was added to the reaction mixture, and themixture was extracted with diethyl ether. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate, and the solventwas removed under reduced pressure. Acetonitrile (5 mL), triethylamine(2.5 g) and isopropylhydrazine hydrochloride (0.55 g) were added to theresidue, and the mixture was stirred at room temperature overnight.Water and diethyl ether was added to the reaction mixture, and theorganic layer was separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The residue was purified by columnchromatography on aminopropylated silica gel (eluent:dichloromethane) togive the title compound (1.8 g).

Process 2

3-Benzyloxy-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-formyl-1-isopropyl-1H-pyrazole

To a solution of3-benzyloxy-5-(2,3-dihydrobenzo-[1,4]dioxin-6-yl)-1-isopropyl-1H-pyrazole(1.8 g) in N,N-dimethylformamide (3 mL) was added phosphorus oxychloride(0.97 g) at 80° C., and the mixture was stirred at 80° C. for 2 hours.After the reaction mixture was cooled to room temperature, a sodiumhydroxide aqueous solution (2 mol/L, 10 mL) was added to the reactionmixture. The mixture was extracted with diethyl ether. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel(eluent:hexane/dichloromethane=1/4-dichloromethane) to give the titlecompound (0.86 g).

Process 3

1-Isopropyl-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-[(4-methoxyphenyl)methyl]-1,2-dihydro-3H-pyrazole-3-one

To a solution of3-benzyloxy-5-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)-5-formyl-1-isopropyl-1H-pyrazole(0.19 g) in tetrahydrofuran (2 mL) was added a solution of4-methoxyphenyl-magnesium bromide in tetrahydrofuran (1 mol/L, 0.60 mL)at room temperature, and the mixture was stirred at room temperature for2 hours. A small amount of water was added to the reaction mixture, andthe mixture was purified by column chromatography on aminopropylatedsilica gel (eluent:tetrahydrofuran). The obtained compound was dissolvedin ethanol (10 mL). Ten percent (10%) Palladium-carbon powder was addedto the solution, and the mixture was stirred at room temperature under ahydrogen atmosphere overnight. Dichloromethane was added to the reactionmixture, and the insoluble material was removed by filtration. Thesolvent of the filtrate was removed under reduced pressure, and ethanoland hexane were added to the residue. The precipitated material wascollected by filtration and dried under reduced pressure to give thetitle compound (0.056 g).

¹H-NMR (CDCl₃) δ ppm:

1.35 (6H, d, J=6.7 Hz), 3.56 (2H, s), 3.75 (3H, s), 4.15-4.35 (5H, m),6.64-6.70 (1H, m), 6.70-6.78 (3H, m), 6.86-6.92 (1H, m), 7.60-7.12 (2H,m)

Process 4

5-(2,3-Dihydrozenzo[1,4]dioxin-6-yl)-3-(β-D-glucopyranosyloxy)-1-isopropyl-4-[(4-methoxyphenyl)methyl-1H-pyrazole

To a suspension of1-isopropyl-5-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)-4-[(4-methoxyphenyl)methyl]-1,2-dihydro-3H-pyrazole-3-one(0.052 g), acetobromo-α-D-glucose (0.28 g) andbenzyl(n-tributyl)ammonium chloride (0.021 g) in dichloromethane (4 mL)was added sodium hydroxide (5 mol/L, 0.27 mL), and the mixture wasstirred at room temperature for 2 hours. The reaction mixture waspurified by column chromatography on aminopropylated silica gel(eluent:tetrahydrofuran). The obtained semi purified5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl-1H-pyrazolewas dissolved in methanol (4 mL), and sodium methoxide (28% methanolsolution, 0.26 mL) was added to the solution. The mixture was stirred atroom temperature for 2 hours. The solvent of the reaction mixture wasremoved, and methanol (1 mL) and 10% citric acidaqueous solution (10 mL)were added to the residue. The mixture was purified by solid phaseextraction on ODS (washing solvent:water, eluent:methanol). Furtherpurification by preparative reverse phase column chromatography(Shiseido CAPSELLPAC C18 UG80, 5μM, 20×50 mm, flow rate 30 mL/min lineargradient, water/methanol=90/10-10/90) gave the title compound (0.022 g).

¹H-NMR (CD₃OD) δ ppm:

1.31 (3H, d, J=6.3 Hz), 1.32 (3H, d, J=6.6 Hz), 3.25-3.50 (4H, m), 3.56(1H, d, J=15.6 Hz), 3.61 (1H, d, J=15.6 Hz), 3.68 (1H, dd, J=5.3, 12.0Hz), 3.72 (3H, s), 3.82 (1H, dd, J=2.2, 12.0 Hz), 4.20-4.35 (5H, m),5.10-5.20 (1H, m), 6.60-6.66 (2H, m), 6.80-6.74 (2H, m), 6.84-6.90 (1H,m), 6.92-6.98 (2H, m)

EXAMPLE 120

The following compound was prepared in a similar manner to thatdescribed in Example 119 using a corresponding starting material.

5-(Benzo[1,3]dioxolene-5-yl)-3-(β-D-glucopyranosyloxy)-1-isopropyl-4-[(4-methoxyphenyl)methyl]-1H-pyrazole

¹H-NMR (CD₃OD) δ ppm:

1.32 (3H, d, J=6.7 Hz), 1.33 (3H, d, J=6.7 Hz), 3.25-3.50 (4H, m), 3.57(1H, d, J=15.7 Hz), 3.61 (1H, d, J=15.7 Hz), 3.65-3.75 (4H, m), 3.82(1H, dd, J=2.5, 12.2 Hz), 4.20-4.35 (1H, m), 5.14-5.22 (1H, m), 5.99(2H, s), 6.60 (1H, d, J=1.8 Hz), 6.65 (1H, dd, J=1.8, 7.9 Hz), 6.68-6.74(2H, m), 6.87 (1H, d, J=8.0 Hz), 6.92-6.98 (2H, m)

EXAMPLE 121

Process 1

3-Benzyoxy-4-bromo-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole

To a solution of3-benzyloxy-1-isopropyl-5-(4-methoxy-phenyl)-1H-pyrazole (3.7 g) indichloromethane (50 mL) was added bromine (0.98 mL) at 0° C., and themixture was stirred for 1 hour. A saturated sodium hydrogen carbonateaqueous solution was added to the reaction mixture, and the organiclayer was separated. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue was purified by column chromatography on silica gel(eluent:hexane/dichloromethane=2/1) to give the title compound (3.3 g).

¹H-NMR (CDCl₃) δ ppm:

1.35 (6H, d, J=6.6 Hz), 3.86 (3H, s), 4.25-4.40 (1H, m), 5.33 (2H, s),6.95-7.05 (2H, m), 7.25-7.40 (5H, m), 7.50-7.55 (2H, m)

Process 2

1-Isopropyl-5-(4-methoxyphenyl)-4-[(2,4-dimethoxyphenyl)-methyl]-1,2-dihydro-3H-pyrazole-3-one

To a solution of3-benzyloxy-4-bromo-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole intetrahydrofuran (2 mL) was added n-butyllithium (2.6 mol/L hexanesolution, 0.89 mL) at −78° C. under argon atmosphere, and the mixturewas stirred for 30 minutes. A solution of 2,4-dimethoxybenzaldehyde(0.51 g) in tetrahydrofuran (2 mL) was added to the reaction mixture,and the mixture was stirred at −78° C. for 1 hour. The reaction mixturewas directly purified by column chromatography on aminopropylated silicagel (eluent:tetrahydrofuran). The obtained semi purified[3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl(2,4-dimethoxyphenyl)methanolwas dissolved in ethanol (9 mL), and a catalytic amount of 10%palladium-carbon powder was added to the solution. The mixture wasstirred at room temperature under a hydrogen atmosphere overnight.Dichloromethane was added to the reaction mixture, and the insolublematerial was removed by filtration. The solvent of the filtrate wasremoved, and diethyl ether and hexane were added to the residue. Theinsoluble material was collected by filtration and dried under reducedpressure to give the title compound (0.09 g).

¹H-NMR (CDCl₃) δ ppm:

1.34 (6H, d, J=6.7 Hz), 3.51 (2H, s), 3,73 (3H, s), 3.76 (3H, s), 3.84(3H, s), 4.10-4.25 (1H, m), 6.30-6.40 (2H, m), 6.90-7.00 (3H, m),7.10-7.20 (2H, m)

Process 3

3-(β-D-Glucopyranosyloxy)-1-isopropyl-5-(4-methoxy-phenyl)-4-[(2,4-dimethoxyphenyl)methyl]-1H-pyrazole

To a suspension of1-isopropyl-5-(4-methoxypheny)-4-[(2,4-dimethoxyphenyl)methyl]-1,2-dihydro-3H-pyrazole-3-one(0.090 g), acetobromo-α-D-glucose (0.48 g) andbenzyl-(n-tributyl)ammonium chloride (0.037 g) in dichloromethane (2 mL)was added sodium hydroxide (5 mol/L, 0.47 mL), and the mixture wasstirred at room temperature for 3 hours. The reaction mixture waspurified by column chromatography on aminopropylated silica gel(eluent:tetrahydrofuran). The obtained semi purified1-isopropyl-5-(4-methoxyphenyl)-4-[(2,4-dimethylphenyl)-methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazolewas dissolved in methanol (5 mL), and sodium methoxide (28% methanolsolution, 0.45 mL) was added to the solution. The mixture was stirred atroom temperature overnight. The solvent of the reaction mixture wasremoved, and methanol (0.5 mL) and 10% citric acid aqueous solution (5mL) were added to the residue. The mixture was purified by solid phaseextraction on ODS (washing solvent:water, eluent:methanol). Furtherpurification by preparative reverse phase column chromatography(Shiseido CAPSELLPAC C18 UG80, 5μM, 20×50 mm, flow rate 30 mL/min lineargradient, water/methanol=90/10-10/90) gave the title compound (0.065 g).

¹H-NMR (CD₃OD) δ ppm:

1.33 (3H, d, J=6.8 Hz), 1.34 (3H, d, J=6.4 Hz), 3.15-3.30 (1H, m),3.30-3.45 (3H, m), 3.51 (1H, d, J=16.8 Hz), 3.55 (1H, d, J=16.8 Hz),3.64 (3H, s), 3.68 (1H, dd, J=5.4, 12.1 Hz), 3.72 (3H, s), 3.75-3.85(4H, m), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.30-6.40 (2H, m),6.80-7.00 (3H, m), 7.00-7.15 (2H, m)

EXAMPLES 122-128

The compounds described in Tables 20-22 were prepared in a similarmanner to that described in Example 121 using corresponding startingmaterials. TABLE 23 Example Chemical number structure ¹H-NMR (CD₃OD) δppm: Example 122

1.26 (3H, t, J=6.9Hz), 1.34 (3H, d, J=6.6Hz), 1.35 (3H, d, J=6.6Hz),3.20-3.30 (1H, m), 3.30-3.45 (3H, m), 3.53 (1H, d, J=16.8Hz), 3.68 (1H,dd, J=5.2, 12.0Hz), .3.71 (3H, s), 3.80 (1H, dd, J=2.4, 12.0Hz), 3.87(2H, q, J=7.0Hz), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.30-6.40 (2H,m), 6.80-6.90 (1H, m), 7.10-7.20 (2H, m), 7.30-7.45 (3H, m) Example 123

1.26 (3H, t, J=7.0Hz), 1.34 (3H, d, J=6.6Hz), 1.35 (3H, d, J=6.6Hz),3.20-3.30 (1H, m), 3.30-3.45 (3H, m), 3.55-3.75 (3H, m), 3.80 (1H, dd,J=2.5, 12.1Hz), 3.85-3.95 (2H, m), 5.10-5.25 (1H, m), 6.65-6.80 (2H, m),6.90-7.00 (1H, m), 7.00-7.10 (1H, m), 7.10-7.20 (2H, m), 7.30-7.40 (3H,m)

TABLE 24 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example124

1.34 (3H, d, J=6.6Hz), 1.35 (3H, d, J=6.3Hz), 3.15-3.30 (1H, m),3.30-3.45 (3H, m), 3.55-3.70 (6H, m), 3.75-7.85 (4H, m), 4.20-4.35 (1H,m), 5.10-5.20 (1H, m), 6.70-6.85 (2H, m), 6.85-7.00 (3H, m), 7.00-7.15(3H, m) Example 125

1.27 (3H, t, J=6.9Hz), 1.34 (3H, d, J=6.6Hz), 1.35 (3H, d, J=6.6Hz),3.15-3.30 (1H, m), 3.30-3.45 (3H, m), 3.61 (1H, d, J=17.0Hz), 3.65 (1H,d, J=17.0Hz), 3.67 (1H, dd, J=5.2, 12.0Hz), 3.75-3.85 (4H, m), 3.85-3.95(2H, m), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.70-7.80 (2H, m),6.85-7.00 (3H, m), 7.00-7.10 (3H, m) Example 126

1.26 (3H, t, J=7.1Hz), 1.33 (3H, d, J=6.6Hz), 1.34 (3H, d, J=6.6Hz),3.15-3.30 (1H, m), 3.30-3.45 (3H, m), 3.52 (1H, d, J=16.7Hz), 3.57 (1H,d, J=16.7Hz), 3.68 (1H, dd, J=5.1, 11.9Hz), 3.71 (3H, s), 3.78 (3H, s),3.80 (1H, dd, J=2.6, 11.9Hz), 3.87 (1H, q, J=7.1Hz), 4.20-4.35 (1H, m),5.10-5.20 (1H, m), 6.30-6.40 (2H, m), 6.80-6.95 (3H, m), 7.00-7.10 (2H,m) Example 127

1.24 (3H, t, J=7.6Hz), 1.30-1.40 (6H, m), 2.67 (2H, q, J=7.6Hz),3.15-3.45 (4H, m), 3.52 (1H, d, J=16.4Hz), 3.56 (1H, d, J=16.4Hz), 3.63(3H, s), 3.68 (1H, dd, J=5.0, 12.0Hz), 3.72 (3H, s), 3.80 (1H, dd,J=2.5, 12.0Hz), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.30-6.40 (2H, m),6.80-6.90 (1H, m), 7.00-7.10 (2H, m), 7.15-7.30 (2H, m) Example 128

1.26 (6H, d, J=6.9Hz), 1.30-1.40 (6H, m), 2.85-3.00 (1H, m), 3.15-3.45(4H, m), 3.52 (1H, d, J=16.7Hz), 3.56 (1H, dd, J=16.7Hz), 3.62 (3H, s),3.68 (1H, dd, J=5.3, 12.0Hz), 3.72 (3H, s), 3.80 (1H, dd, J=2.5,12.0Hz), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.30-6.40 (2H, m),6.80-6.90 (1H, m), 7.00-7.10 (2H, m), 7.20-7.30 (2H, m)

EXAMPLE 129

Process 1

3-Hydroxy-1-isopropylpyrazole-4-carboxylic acid ethyl ester

To a solution of sodium ethoxide (23 g) in ethanol (150 mL) were addedethoxymethylene malonic acid diethyl ester (32.7 g) andisopropylhydrazine (11.2 g) at room temperature, and the mixture wasstirred at 80° C. for 4 hours and then at 100° C. for 2 hours. Thereaction mixture was poured into 2 mol/L hydrochloric acid (300 mL), themixture was diluted with brine and extracted with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure, and theobtained residue was purified by column chromatography on silica gel(eluent:ethyl acetate/hexane=1/5 ) to give the title compound (10.5 g).

¹H-NMR (CDCl₃) δ ppm:

1.35 (3H, t, J=7.0 Hz), 1.48 (6H, d, J=6.7 Hz), 4.20-4.40 (3H, m), 7.60(1H, s)

Process 2

5-Bromo-3-hydroxy-1-isopropylpyrazole-4-carboxylic acid ethyl ester

3-Hydroxy-1-isopropylpyrazole-4-carboxylic acid ethyl ester (10.5 g) wasdissolved in dichloromethane (100 mL), and N-bromosuccinimide (14.1 g)was added to the solution under ice cooling. The mixture was stirred atroom temperature for 6 hours. The solvent was removed under reducedpressure, and the obtained residue was purified by column chromatographyon silica gel (eluent:ethyl acetate/hexane=1/5) to give the titlecompound (5.9 g)

¹H-NMR (CDCl₃) δ ppm:

1.39 (3H, t, J=7.0 Hz), 1.44 (6H, d, J=6.6 Hz), 4.37 (2H, q, J=7.0 Hz),4.60-4.80 (1H, m), 8.34 (1H, s)

Process 3

3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid ethyl ester

5-Bromo-3-hydroxy-1-isopropylpyrazole-4-carboxylic acid ethyl ester (5.8g) and potassium carbonate (3.5 g) were suspended inN,N-dimethylformamide (50 mL), and benzyl bromide (2.76 mL) was added tothe suspension under ice cooling. The mixture was stirred at roomtemperature for 6 hours. The reaction mixture was poured into 1 mol/Lhydrochloric acid (100 mL), and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the obtained residue was purified by column chromatographyon silica gel (eluent:ethyl acetate/hexane=1/5) to give the titlecompound (7.7 g)

¹H-NMR (CDCl₃) δ ppm:

1.35(3H, t, J=7.1 Hz), 1.42 (6H, d, J=6.6 Hz), 4.30 (2H, q, J=7.1 Hz),4.60-4.80 (1H, m), 5.32 (2H, s), 7.20-7.60 (5H, m)

Process 4

3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid

3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid ethyl ester(7.7 g) was suspended into 1,4-dioxan (19 mL), and 20% sodium hydroxideaqueous solution (19 mL) was added to the suspension. The mixture wasstirred at 100° C. for 8 hours. After the mixture was cooled, thereaction mixture was poured into 2 mol/L hydrochloric acid (100 mL). Themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give the title compound (4.6 g).

¹H-NMR (CDCl₃) δ ppm:

1.43 (6H, d, J=6.7 Hz), 4.60-4.85 (1H, m), 5.34 (2H, s), 7.20-7.65 (5H,m)

Process 5

3-Benzyloxy-5-bromo-4-hydroxymethyl-1-isopropyl-1H-pyrazole

3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid (4.6 g) wasdissolved in tetrahydrofuran (30 mL), and borane-tetrahydrofurancomplex, 1M tetrahydrofuran solution (21 mL) was delivered by drops intothe stirred solution under ice cooling. The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was cooled with ice bath,and water (50 mL) was delivered by drops into the mixture. Hydrochloricacid (1 mol/L, 20 mL) was delivered by drops into the mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the obtained residue was purified bycolumn chromatography on silica gel (eluent:ethyl acetate/hexane =1/5)to give the title compound (3.0 g).

¹H-NMR (CDCl₃) δ ppm:

1.41 (6H, d, J=6.6 Hz), 1.51 (1H, t, J=6.1 Hz), 4.43 (2H, d, J=6.1 Hz),4.50-4.68 (1H, m), 5.25 (2H, s), 7.20-7.60 (5H, m)

Process 6

3-Benzyloxy-5-bromo-4-formyl-1-isopropyl-1H-pyrazole

3-Benzyloxy-5-bromo-4-hydroxymethyl-1-isopropyl-1H-pyrazole (3.0 g) wasdissolved in dichloromethane (30 mL), and manganese dioxide (4 g) wasadded to the stirred solution at room temperature. The mixture wasstirred at 50° C. for 1 hour. After the insoluble material was removedby filtration, the filtrate was concentrated under reduced pressure togive the title compound (2.7 g).

¹H-NMR (CDCl₃) δ ppm:

1.44 (6H, d, J=6.7 Hz), 4.55-4.75 (1H, m), 5.34 (2H, s), 7.20-7.60 (5H,m), 9.75 (1H, s)

Process 7

3-Benzyloxy-5-bromo-4-[hydroxyl(4-methoxyphenyl)methyl]-1-isopropyl-1H-pyrazole

3-Benzyloxy-5-bromo-4-formyl-1-isopropyl-1H-pyrazole (0.7 g) wasdissolved in tetrahydrofuran (5 mL), and a solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (0.5 mL/L, 4.3 mL) was added to thestirred solution. The mixture was stirred at room temperature for 1hour. A small amount of a saturated ammonium chloride aqueous solutionwas added to the reaction mixture, and the mixture was purified bycolumn chromatography on aminopropylated silica gel(eluent:tetrahydrofuran) to give the title compound (0.6 g).

¹H-NMR (CDCl₃) δ ppm:

1.40 (6H, d, J=6.6 Hz),2.65 (1H, d, J=7.5 Hz), 3.79 (3H, s),4.45-4.65(1H, m), 5.15-5.35 (2H, m), 5.66 (1H, d, J=7.5Hz), 6.83 (2H, d, J=9.0Hz), 7.20-7.45 (7H, m)

Process 8

3-Benzyloxy-5-bromo-1-isopropyl-4-(4-methoxybenzoyl)-1H-pyrazole

3-Benzyloxy-5-bromo-4-[hydroxyl(4-methoxyphenyl)-methyl]-1-isopropyl-1H-pyrazole(0.6 g) was dissolved in dichloromethane (10 mL), and manganese dioxidewas added to the stirred solution at room temperature. The mixture wasstirred at 50° C. for 1 hour. The insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure togive the title compound (0.4 g).

¹H-NMR (CDCl₃) δ ppm:

1.47 (6H, d, J=6.6 Hz), 3.86 (3H, s), 4.60-4.80 (1H, m), 5.23 (2H, s),6.87 (2H, d, J=8.9 Hz), 7.15-7.40 (5H, m), 7.81 (2H, d, J=8.9 Hz)

Process 9

3-Benzyloxy-5-[4-(N,N-dimethylamino)phenyl]-1-isopropyl-4-(4-methyoxybenzoyl)-1H-pyrazole

A suspension of3-benzyloxy-5-bromo-1-isopropyl-4-(4-methoxybenzoyl)-1H-pyrazole (0.11g), 4-N,N-dimethylamino)-phenylboronic acid (0.061 g),tetrakis(triphenylphosphine)-palladium (0.034 g), potassium carbonate(0.078 g) and water (0.2 mL) in N,N-dimethylformamide (4 mL) was stirredat 80° C. for 12 hours. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate, and the solventwas removed under reduced pressure. The residue was purified by columnchromatography on aminopropylated silica gel (eluent:hexane/ethylacetate=5/1) to give the title compound (0.098 g).

Process 10

5-[4-(N,N-Dimethylamino)phenyl]-1-isopropyl-4-(4-methoxyphenyl)methyl-3H-pyrazole-3-onhydrochloride

To a suspension of sodium borohydride (0.016 g) in tetrahydrofuran (4mL) was added3-benzyloxy-5-[4-(N,N-dimethylamino)phenyl]-1-isopropyl-4-(4-methoxybenzoyl)-1H-pyrazole(0.098 g) in tetrahydrofuran (1 mL) at 0° C., and the mixture wasstirred for 1 hour. Diluted hydrochloric acid was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine and dried over anhydrous magnesium sulfateand the solvent was removed under reduced pressure. The residue wasdissolved in methanol (5 mL), and 10% palladium-carbon powder (10 mg)and a hydrochloric acid aqueous solution (2 mol/L, 0.1 mL) were added tothe solution. The mixture was stirred at room temperature under ahydrogen atmosphere for 6 hours. The insoluble material was removed byfiltration and the solvent of the filtrate was removed under reducedpressure to give the title compound (0.051 g).

Process 11

1-Isopropyl-4-(4-methoxyphenylmethyl)-5-[4-(N,N-dimethyl-amino)phenyl]-3-(β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of5-[4-(N,N-dimethylamino)phenyl]-1-isopropyl-4-(4-methoxyphenyl)methyl-3H-pyrazole-3-onhydrochloride (0.051 g), acetobromo-α-D-glucose (0.16 g) andbenzyl(n-tributyl)ammonium chloride (0.12 g) in dichloromethane (3 mL)was added sodium hydroxide (2 mol/L, 0.19 mL), and the mixture wasstirred at room temperature for 3 hours. The reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on aminopropylated silica gel (eluent:ethyl acetate). Theobtained semi purified1-isopropyl-4-(4-methoxyphenylmethyl)-5-[4-(N,N-dimethyl-amino)phenyl]-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazoelwas dissolved in methanol, and sodium methoxide (28% methanol solution,0.02 mL) was added to the solution. The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and the residue was purified by preparative reversephase column chromatography (Shiseido CAPSELLPAC C18UG80, 5μM, 20×50 mm,flowrate 30 mL/min linear gradient, water/methanol=90/10-10/90) to givethe title compound (0.040 g).

¹H-NMR (CD₃OD) δ ppm:

1.32 (3H, d, J=6.6 Hz), 1.33 (3H, d, J=6.6 Hz),2.97 (6H, s), 3.25-3.50(4H, m), 3.56 (1H, d, J=15.6 Hz), 3.61 (1H, d, J=15.6 Hz), 3.68 (1H, dd,J=5.7, 12.1 Hz), 3.72 (3H, s), 3.81 (1H, dd, J=2.7, 12.1 Hz), 4.25-4.35(1H, m), 5.10-5.20 (1H, m), 6.65-6.75 (2H, m), 6.75-6.85 (2H, m),6.90-7.10 (4H, m)

EXAMPLES 130-139

The compounds described in Tables 25-27 were prepared in a similarmanner to that described in Example 129 using corresponding startingmaterials and optionally introducing a protective group. TABLE 25Example Chemical number structure ¹HNMR (CD₃OD) δ ppm: Example 130

1.35 (3H, d, J=6.7Hz), 1.36 (3H, d, J=6.7Hz), 3.25-3.50 (4H, m), 3.59(1H, d, J=14.9Hz), 3.65 (1H, d, J=14.9Hz), 3.71(1H, dd, J=5.2, 12.0Hz),3.71 (3H, s), 3.84 (1H, dd, J=2.4, 12.0Hz), 4.10-4.25 (1H, m), 5.25-5.35(1H, m), 6.65-6.75 (2H, m), 6.85-6.95 (2H, m), 7.45-7.55 (1H, m),7.60-7.70 (1H, m), 8.25-8.35 (1H, m), 8.50-8.60 (1H, m) Example 131

1.25-1.40 (6H, m), 2.95 (6H, s), 3.10-3.25 (1H, m), 3.28-3.43 (3H, m),3.60-3.70 (4H, m), 3.73 (3H, s), 3.78 (1H, dd, J=2.3Hz, 12.2Hz),4.25-4.40 (1H, m), 5.09 (1H, d, J=7.5Hz), 6.35 (1H, dd, J=2.3Hz, 8.5Hz),6.38 (1H, d, J=2.3Hz), 6.74 (2H, d, J=9.0Hz), 6.83 (1H, d, J=8.5Hz),6.99 (2H, d, J=9.0Hz)

TABLE 26 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example132

1.25-1.45 (6H, m), 3.24-3.50 (4H, m), 3.55-3.65 (6H, m), 3.69 (1H, dd,J=5.4Hz, 12.0Hz), 3.72 (3H, s), 3.82 (1H, dd, J=2.6Hz, 12.0Hz),4.25-4.45 (1H, m), 5.26 (1H, d, J=7.8Hz), 6.25-6.40 (2H, m), 6.89 (1H,d, J=9.0Hz), 7.23 (2H, d, J=6.1Hz), 8.55 (2H, d, J=6.1Hz) Example 133

1.30-1.40 (6H, m), 3.25-3.45 (4H, m), 3.52-3.62 (5H, m), 3.65-3.75 (4H,m), 3.82 (1H, dd, J=2.3Hz, 12.1Hz), 3.92 (3H, s), 4.15-4.30 (1H, m),5.22 (1H, d, J=7.6Hz), 6.25-6.40 (2H, m), 6.87 (1H, d, J=8.6Hz), 7.28(2H, d, J=8.4z), 8.02 (2H, d, J=8.4Hz) Example 134

1.25-1.40 (6H, m), 3.25-3.50 (4H, m), 3.52-3.64 (5H, m), 3.69 (1H, dd,J=5.3Hz, 12.1Hz), 3.72 (3H, s), 3.82 (1H, dd, J=2.3Hz, 12.1Hz),4.15-4.32 (1H, m), 5.21 (1H, d, J=7.8Hz), 6.25-6.40 (2H, m), 6.87 (1H,d, J=9.0Hz), 7.25 (2H, d, J=8.0Hz), 8.01 (2H, d, J=8.0Hz) Example 135

1.30-1.45 (6H, m), 3.15-3.47 (4H, m), 3.51-3.63 (2H, m), 3.67 (1H, dd,J=5.1Hz, 12.1Hz), 3.69 (3H, s), 3.73 (3H, s), 3.79 (1H, dd, J=2.3Hz,12.1Hz), 4.25-4.45 (1H, m), 5.13 (1H, d, J=7.3Hz), 6.35 (1H, dd,J=2.4Hz, 8.3Hz), 6.41 (1H, d, J=2.4Hz), 6.84 (2H, d, J=8.3Hz), 6.96 (1H,dd, J=0.9Hz, 4.7Hz), 7.25 (1H, dd, J=0.9Hz, 2.9Hz), 7.48 (1H, dd,J=2.9Hz, 4.7Hz) Example 136

1.30-1.45 (6H, m), 3.10-3.50 (4H, m), 3.52-3.64 (2H, m), 3.67 (1H, dd,J=5.2Hz, 12.0Hz), 3.69 (3H, s), 3.73 (3H, s), 3.79 (1H, dd, J=2.6Hz,12.0Hz), 4.35-4.55 (1H, m), 5.17 (1H, d, J=7.7Hz), 6.34 (1H, dd,J=2.2Hz, 8.2Hz), 6.40 (1H, d, J=2.2Hz), 6.80 (2H, d, J=8.2Hz), 6.94 (1H,dd, J=1.0Hz, 3.7Hz), 7.09 (1H, dd, J=3.7Hz, 5.2Hz), 7.54 (1H, dd,J=1.0Hz, 5.2Hz)

TABLE 27 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example137

1.25-1.45 (6H, m), 3.01 (3H, s), 3.10 (3H, s), 3.15-3.47 (4H, m),3.53-3.62 (2H, m), 3.64 (3H, s), 3.66-3.75 (4H, m), 3.82 (1H, dd,J=2.1Hz, 12.0Hz), 4.15-4.35 (1H, m), 5.20 (1H, d, J=7.7Hz), 6.25-6.40(2H, m), 6.84 (1H, d, J=8.1Hz), 7.26 (2H, d, J=8.3Hz), 7.44 (2H, d,J=8.3Hz) Example 138

1.25-1.45 (6H, m), 2.92 (3H, s), 3.15-3.47 (4H, m), 3.51-3.58 (2H, m),3.60 (3H, s), 3.68 (1H, dd, J=5.2Hz, 11.9Hz), 3.72 (3H, s), 3.81 (1H,dd, J=2.1Hz, 11.9Hz), 4.15-4.35 (1H, m), 5.20 (1H, d, J=7.1Hz),6.25-6.40 (2H, m), 6.86 (1H, d, J=8.7Hz), 7.26 (2H, d, J=8.2Hz), 7.81(2H, d, J=8.2Hz) Example 139

1.25-1.45 (6H, m), 3.15-3.47 (4H, m), 3.52-3.65 (5H, m), 3.69 (1H, dd,J=4.8Hz, 12.0Hz), 3.72 (3H, s), 3.81 (1H, dd, J=2.2Hz, 12.0Hz),4.15-4.35 (1H, m), 5.20 (1H, d, J=7.4Hz), 6.25-6.40 (2H, m), 6.87 (1H,d, J=8.2Hz), 7.27 (2H, d, J=8.2Hz), 7.88 (2H, d, J=8.2Hz)

EXAMPLE 140

Process 1

[3-Benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole-4-yl](2-methoxy-4-triisopropylsilyloxyphenyl)methanol

To a solution of3-benzyloxy-4-bromo-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole (2.4 g)in tetrahydrofuran (15 mL) was added n-butyllithium (2.66 mol/L,tetrahydrofuran solution, 2.2 mL) at −78° C. under an argon atmosphere,and the mixture was stirred for 30 minutes. A solution of2-methoxy-4-triisopropyl-silyloxybenzaldehyde (2.0 g) in tetrahydrofuran(3 mL) was added to the reaction mixture and the mixture was stirred at−78° C. for 30 minutes. The reaction mixture was purified by columnchromatography on aminopropylated silica gel (eluent:tetrahydrofuran),and further purification by column chromatography on silica gel(eluent:hexane/ethyl acetate) gave the title compound (3.0 g).

Process 2

5-(4-Methoxypheny)-1-isopropyl-4-(2-methoxy-4-triisopropyl-silyloxyphenyl)methyl-3H-pyrazole-3-on

To a solution of[3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole-4-yl](2-methoxy-4-triisopropyl-silyloxyphenyl)methanol (3.0 g) in ethanol wasadded a catalytic amount of 10% palladium-carbon powder, and the mixturewas stirred at room temperature under a hydrogen atmosphere overnight.Dichloromethane (20 mL) was added to the reaction mixture and theinsoluble material was removed by filtration. The solvent of thefiltrate was removed under reduced pressure and hexane was added to theresidue. The insoluble material was collected by filtration and driedunder reduced pressure to give the title compound (1.8 g).

¹H-NMR (CDCl₃) δ ppm:

1.09 (18H, d, J=7.2 Hz), 1.15-1.30 (3H, m), 1.33 (6H, d, J=6.6 Hz), 3.48(2H, s), 3.74 (3H, s), 3.85 (3H, s), 4.10-4.25 (1H, m), 6.30-6.40 (2H,m), 6.75-6.80 (1H, m), 6.90-7.00 (2H, m), 7.10-7.20 (2H, m)

Process 3

3-(2,3,4,6-Tetrapivaroyl-β-D-glucopyranosyloxy)-1-isopropyl-5-(4-methoxypheny)-4-[(4-hydroxy-2-methoxyphenyl)-methyl]-1H-pyrazole

To a suspension of5-(4-methoxyphenyl)-1-isopropyl-4-(2-methoxy-4-triisopropylsilyloxyphenyl)methyl-3H-pyrazole-3-on(1.5 g), 2,3,4,6-tetrapivaroyl-1-bromo-α-D-glucose (9.2 g) andbenzyl(n-tributyl)ammonium chloride (0.46 g) in dichloromethane (2 mL)was added sodium hydroxide (5 mol/L, 5.9 mL) and the mixture was stirredat room temperature for 2 hours. The reaction mixture was purified bycolumn chromatography on aminopropylated silica gel(eluent:tetrahydrofuran). Further purification by column chromatographyon silica gel (eluent:dichloromethane—hexane/ethyl acetate=8/1) gave1-isopropyl-5-(4-methoxyphenyl)-4-[(2-methoxy-4-triisopropyloxypheny)methyl]-3-(2,3,4,6-tetra-O-pivaroyl-β-D-glucopyranosyloxy)-1H-pyrazole.The obtained1-isopropyl-5-(4-methoxyphenyl)-4-[(2-methoxy-4-triisopropyloxypheny)-methyl]-3-(2,3,4,6-tetra-O-pivaroyl-β-D-glucopyranosyloxy)-1H-pyrazolewas dissolved in tetrahydrofuran (10 mL), and tetra-n-butylammoniumfluoride (1 mol/L tetrahydrofuran solution, 3.5 mL) was added to thesolution. The mixture was stirred at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel(eluent:hexane/ethyl acetate=4/1-3/1-1/1) to give the desired titlecompound (0.82 g).

¹H-NMR (CDCl₃) δ ppm:

1.08 (9H, s), 1.12 (9H, s), 1.15 (9H, s), 1.19 (9H, s), 1.29 (1H, d,J=6.7 Hz), 1.32 (1H, d, J=6.7 Hz), 3.42 (1H, d, J=16.3 Hz), 3.46 (1H, d,J=16.3 Hz), 3.59 (3H, s), 3.75-3.85 (1H, m), 3.82 (3H, s), 4.10 (1H, dd,J=4.7, 12.2 Hz), 4.17 (1H, dd, J=1.7, 12.2 Hz), 4.15-4.25 (1H, m),5.15-5.30 (2H, m), 5.35-5.45 (1H, m), 5.77 (1H, d, J=8.1 Hz), 6.15-6.30(2H, m), 6.75-6.85 (1H, m), 6.85-6.95 (2H, m), 7.00-7.10 (2H, m)

Process 4

1-Isopropyl-5-(4-methoxyphenyl)-4-[(2-methoxy-4-carbamoyl-methyloxypheny)methyl]-3-(2,3,4,6-tetra-O-pivaroyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of3-(2,3,4,6-tetrapivaroyl-β-D-glucopyranosyloxy)-1-isopropyl-5-(4-methoxyphenyl)-4-[(4-hydroxy-2-methoxyphenyl)methyl]-1H-pyrazole(0.13 g) and cesium carbonate (0.10 g) in N,N-dimethylformamide (1 mL)was added 2-bromoacetoamide (0.031 g), and the mixture was stirred atroom temperature for 2 hours. Water (10 mL) was added to the reactionand the mixture was stirred at room temperature. After 1 hour,theprecipitated solid was collected by filtration and dried under reducedpressure to give the title compound (0.13 g).

Process 5

1-Isopropyl-5-(4-methoxyphenyl)-4-[(2-methoxy-4-carbamoylmethyloxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-isopropyl-5-(4-methoxyphenyl)-4-[(2-methoxy-4-carbamoylmethyloxyphenyl)methyl]-3-(2,3,4,6-tetra-O-pivaroyl-p-β-glucopyranosyloxy)-1H-pyrazole(0.13 g) in methanol (2 mL) was added sodium methoxide (28% methanolsolution, 0.13 mL), and the mixture was stirred at 55° C. for 30minutes. A citric acid aqueous solution (10%) was added to the reactionmixture, and the mixture was purified by solid phase extraction on ODS(washing solvent:water, eluent:methanol). Further purification bypreparative reverse phase column chromatography (Shiseido CAPSELLPAC C18UG80, 5 μM, 20×50 mm, flow rate 30 mL/min linear gradient,water/methanol=90/10-10/90) gave the title compound (0.051 g).

¹H-NMR (CD₃OD) δ ppm:

1.33 (3H, d, J=6.3 Hz), 1.34 (3H, d, J=6.8 Hz), 3.15-3.30 (1H, m),3.30-3.45 (3H, m), 3.45-3.60 (2H, m), 3.60-3.75 (4H, m), 3.75-3.85 (4H,m), 4.20-4.35 (1H, m), 4.43 (2H, s), 5.05-5.20 (1H, m), 6.35-6.40 (1H,m), 6.45-6.55 (1H, m), 6.80-6.90 (1H, m), 6.90-7.00 (2H, m), 7.00-7.10(2H, m)

EXAMPLES 141-142

The compounds described in Table 28 were prepared in a similar manner tothat described in Example 140 using corresponding starting materials.TABLE 28 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example141

1.25 (3H, t, J=7.6Hz), 1.30-1.40 (6H, m), 2.67 (1H, q, J=7.6Hz),3.10-3.45 (4H, m), 3.45-3.60 (2H, m), 3.60-3.75 (5H, m), 3.79 (1H, dd,J=2.1, 11.9Hz), 4.20-4.35 (1H, m), 4.43 (2H, s), 5.10-5.20 (1H, m),6.35-6.40 (1H, m), 6.45-6.55 (1H, m), 6.85-6.95 (1H, m), 7.00-7.10 (2H,m), 7.20-7.30 (2H, m) Example 142

1.26 (6H, d, J=6.9Hz), 1.30-1.40 (6H, m), 2.80-3.00 (1H, m), 3.15-3.3.45(4H, m), 3.50-3.60 (2H, m), 3.64 (3H, s), 3.67 (1H, dd, J=5.4, 12.0Hz),3.80 (1H, dd, J=2.1, 12.0Hz), 4.20-4.35 (1H, m), 4.43 (2H, s), 5.10-5.20(1H, m), 6.35-6.40 (1H, m), 6.45-6.50 (1H, m), 6.85-6.95 (1H, m),7.05-7.10 (2H, m), 7.20-7.30 (2H, m)

EXAMPLE 143

Process 1

3-(2,3,4,6-Tetrapivaroyl-β-D-glucopyranosyloxy)-1-isopropyl-5-(4-methoxyphenyl)-4-{[4-(2-benzyloxyethyloxy)-2-methoxy-phenyl]methyl}-1H-pyrazole

To a suspension of3-(2,3,4,6-tetrapivaroyl-β-D-glucopyranosyloxy)-1-isopropyl-5-(4-methoxyphenyl)-4-[(4-hydroxy-2-methoxypheny)methyl]-1H-pyrazole(0.13g) and cesium carbonate (0.10 g) in N,N-dimethylformamide (1 mL)was added benzyl 2-bromoethyl ether (0.049 g), and the mixture wasstirred at room temperature for 2 hours. Water was added to the reactionmixture, and the mixture was extracted with dichloromethane. The solventof the organic layer was removed under reduced pressure, and the residuewas purified by column chromatography on silica gel (eluent:hexane/ethylacetate=4/1) to give the title compound (0.11 g).

Process 2

3-(β-D-Glucopyranosyloxy)-1-isopropyl-5-(4-methoxyphenyl)-4-{[4-(2-hydoxyethyloxy)-2-methoxyphenyl]methyl}-1H-pyrazole

To a solution of3-(2,3,4,6-tetrapivaroyl-β-D-glucopyranosyloxy)-1-isopropyl-5-(4-methoxyphenyl)-4-{[4-(2-benzyloxyethyloxy)-2-methoxyphenyl]methyl}-1H-pyrazole(0.11 g) in methanol (2 mL) was added sodium methoxide(28% methanolsolution, 0.13 mL), and the mixture was stirred at 55° C. for 30minutes. A citric acid aqueous solution (10%) was added to the reactionmixture and the mixture was purified by solid phase extraction on ODS(washing solvent:water, eluent:methanol). The obtained semi purified3-(β-D-glucopyranosyloxy)-1-isopropyl-5-(4-methoxyphenyl)-4-{[4-(2-benzyloxyethyloxy)-2-methoxyphenyl]methyl}-1H-pyrazolewas dissolved in methanol (2 mL), a catalytic amount of 10%palladium-carbon powder was added to the solution. The mixture wasstirred at room temperature for 1 hour. The insoluble material wasremoved by filtration, and the solvent of filtrate was removed underreduced pressure. The residue was purified by preparative reverse phasecolumn chromatography (Shiseido CAPSELLPAC C18 UG80, 5 μM, 20×50 mm,flow rate 30 mL/min linear gradient, water/methanol=90/10-10/90) to givethe title compound (0.043 g).

¹H-NMR (CD₃OD) δ ppm:

1.33 (3H, d, J=6.7 Hz), 1.34 (3H, d, J=6.8 Hz), 3.15-3.45 (4H, m), 3.51(1H, d, J=16.2 Hz), 3.55 (1H, d, J=16.2 Hz), 3.60-3.70 (4H, m),3.75-3.85 (6H, m), 3.95-4.05 (2H, m), 4.20-4.35 (1H, m), 5.05-5.20 (1H,m), 6.30-6.40 (1H, m), 6.40-6.45 (1H, m),6.80-6.87 (1H, m), 6.90-7.00(2H, m), 7.05-7.10 (2H, m)

EXAMPLES 144-148

The compounds described in Table 29 were prepared in a similar manner tothat described in Example 143 using corresponding starting materials.TABLE 29 Example Chemical number structure ¹H-NMR (CD₃OD) δ ppm: Example144

1.25 (6H, t, J=7.7Hz), 1.30-1.40 (6H, m), 2.67 (1H, q, J=7.7Hz),3.15-3.45 (4H, m), 3.51 (1H, d, J=16.6Hz), 3.56 (1H, d, J=16.6Hz), 3.63(3H, s), 3.67 (1H, dd, J=1H, dd, J=5.4, 12.0Hz), 3.80 (1H, dd, J=2.6,12.0Hz), 3.80-3.85 (2H, m), 3.95-4.05 (2H, m), 4.20-4.35 (1H, m),5.10-5.20 (1H, m), 6.40-6.6.39 (1H, m), 6.40-6.45 (1H, m), 6.80-6.90(1H, # m), 7.00-7.10 (2H, m), 7.20-7.25 (2H, m) Example 145

1.26 (6H, d, J=7.0Hz), 1.30-1.40 (6H, m), 2.85-3.00 (1H, m), 3.15-3.45(4H, m), 3.45-3.60 (2H, m), 3.63 (3H, s), 3.68 (1H, dd, J=5.2, 12.0Hz),3.75-3.85 (3H, m), 3.95-7.05 (2H, m), 4.20-4.35 (1H, m), 5.10-5.20 (1H,m), 6.30-6.45 (2H, m), 6.80-6.90 (1H, m), 7.00-7.15 (2H, m), 7.20-7.30(2H, m) Example 146

1.33 (3H, d, J=6.5Hz), 1.34(3H, d, J=6.6Hz), 1.90-2.00 (1H, m),3.15-3.45 (4H, m), 3.50 (1H, d, J=16.4Hz), 3.55 (1H, d, J=16.4Hz),3.60-3.75 (6H, m), 3.75-3.85 (2H, m), 4.20-4.35 (1H, m), 5.10-5.15 (1H,m), 6.30-6.40 (2H, m), 6.80-6.85 (1H, m), 6.90-7.00 (2H, m), 7.05-7.15(2H, m) Example 147

1.25 (3H, t, J=7.6Hz), 1.33 (3H, d, J=6.4Hz), 1.34 (3H, d, J=6.8Hz),1.90-2.00 (1H, m), 2.60-2.75 (2H, q, J=7.6Hz), 3.15-3.45 (I4H, m), 3.51(1H, d, J=16.5Hz), 3.55 (1H, d, J=16.5Hz), 3.63 (3H, s), 3.67 (3H, dd,J=5.0, 12.0Hz), 3.72 (2H, t, J=6.4Hz), 3.80 (1H, dd, J=2.2Hz, 12.0Hz),4.01 (2H, # t, 6.4Hz), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.30-6.40(2H, m), 6.80-6.90 (1H, m), 7.00-7.10 (2H, m), (2H, m), 7.20-7.25 (2H,m) Example 148

1.26 (6H, d, J=7.0Hz), 1.33 (3H, d, J=6.5Hz), 1.34 (3H, d, J=6.4Hz),1.90-2.00 (2H, m), 2.85-3.00 (1H, m), 3.15-3.45 (4H, m), 3.51 (1H, d,J=16.6Hz), 3.56 (1H, d, J=16.6Hz), 3.62 (3H, s), 3.68 (1H, dd, J=5.5,12.0Hz), 3.72 (2H, t, J=6.3Hz), 3.80 (1H, dd, J=2.7, 12.0H), 4.01 (2H,t, J=6.2Hz), 4.20-4.35 (1H, m), 5.10-5.20 (1H, m), 6.30-6.40 (2H, # m),6.80-6.90 (1H, m), 7.05-7.10 (2H, m), 7.20-7.30 (2H, m)

TEST EXAMPLE 1

Distribution Pattern of SMINT Gene Expression Among Human Organs

1) cDNA Synthesis

Total RNA (tRNA) from human liver, colon, testis, pancreas, lung, smallintestine, stomach, placenta, and skeletal muscle were obtained fromSawady Technology, and tRNA from the trachea, brain, kidney and heartwere purchased from CLONTECH. Concentrations of these tRNAs weredetermined by using RiboGreen RNA quantification reagent and kit(Molecular Probes), and then each of cDNA was synthesized (i.e.reverse-transcription reaction). Reaction mixture at a volume of 16.5μL, which included 1.5 μg of tRNA and 1.5 μL of 500 ng/μL random hexamer(Invitrogen), was incubated at 70° C. for 5 minutes, then kept at roomtemperature for 5 minutes. After the incubation, to the above reactionmixture was added 13.5 μL of another reaction mixture containing 6 μL of5×BRL 1^(st) strand buffer (Invitrogen), 3.25 μL of distilled water(Nippon Gene), 1.5 μL of 10 mM dNTP mix (Invitrogen), 0.75 μL of RNaseinhibitor (Invitrogen), and 2 μL of SuperScript II (Invitrogen).Simultaneously, another reaction mixture added 2 μL of distilled water(Nippon Gene) instead of the same volume of SuperScript II (Invitrogen)was mixed similarly with the above reaction mixture. All of the mixtureswere incubated at room temperature for 10 minutes followed by thereaction at 42° C. for 1 hour. After the reaction, these mixtures wereincubated at 95° C. for 10 minutes to inactivate SuperScript II(Invitrogen) immediately followed by standing on ice. Then, to themixtures was added 1.5 μL of RNase H, and the mixture was incubated at37° C. for 30 minutes. After the reactions, to the mixtures was added170 μL of distilled water. The synthesized cDNA were extracted with 200μL of phenol:chloroform:isoamylalcohol=25:24:1 (Invitrogen), andextracted again with 200 μL of chloroform:isoamylalcohol=24:1. Afterethanol precipitation, the cDNA were diluted in 100 μL of distilledwater (Nippon Gene).

2) Determination of SMINT Gene Expression By Real-Time Quantitative PCR

Primer sequences used for real-time quantitative PCR were as follows:Forward primer: 5′-TGT CAC AGT CCC CAA CAC CA-3′, Reverse primer: 5′-CCGAAG CAT GTG GAA AGC A-3′, and Probe: 5′-TGT CAC CTC CCA CGG CCC G-3′.The probe was labeled its 5′-end with fluorescence dye FAM, and its3′-end with fluorescence dye TAMRA. Twenty-five μL of reaction mixturewas prepared with 2.5 ng of cDNA prepared as described above, 1×TaqmanUniversal master mix (Applied Biosystems), 500 nM each of the forwardand the reverse primers, and 200 nM of the probe. PCR condition was asfollows: 1 cycle at 50° C. for 2 minutes, 1 cycle at 95° C. for 10minutes, and 40 cycles at 95° C. for 15 seconds and at 60° C. for 1minutes. Gene expression level was detected by GeneAmp 5700 SequenceDetection System (Applied Biosystems) in reaction tubes composed ofMicroAmp optical 96-well reaction plate (Applied Biosystems) andMicroAmp optical cap (Applied Biosystems). Fluorescence signals weredetected according to the manufacturer's instruction (Christian A. Heid,et al., in “Genome Research”, 1996, Vol. 6, pp. 986-994). Serially10-fold diluted plasmid DNA (3.5×10⁶, 3.5×10⁵, 3.5×10⁴, 3.5×10³, 3.5×10²and 3.5×10 molecules/well, extracted from Escherichia coli/SMINT2010324host cells, which is described in Test Example 2) was used to draw astandard curve for the expression analysis. The obtained results wereshown in FIG. 1. FIG. 1 indicates that human SMINT gene is expressedhighly in the small intestine and the kidney. Therefore, human SMINTplays important roles in sugar absorption at the small intestine, sugarreabsorption and/or sugar uptake into the cells at the kidney.

TEST EXAMPLE 2

Confirmatory Test for Substrate Specificity of Human SMINT

1) Preparation of Cells Transiently Expressing Human SMINT

Human SMINT-carrying expression plasmid SMINT/pME18S-FL (denotation ofbacteria: Escherichia coli/ SMINT2010324), which was deposited with NITEPatent Microorganisms Depositary on Mar. 12, 2002, was transfected toCOS-7 cells (RIKEN CELL BANK RCB0539) by lipofection method.LIPOFECTAMINE PLUS reagent (Invitrogen) was used as the lipofectionreagent. A day before the lipofection, COS-7 cells were suspended inD-MEM medium (Invitrogen) at 6×10⁶ cells per 1 mL, and dispensed 50 μLper well of 96-well plate. The lipofection was performed by thefollowing methods. For each well, 0.1 μg of the plasmid was diluted with10 μL of D-MEM, added 0.5 μL of PLUS reagent, mixed gently, and keptstand for 15 minutes to prepare Plasmid Dilute Solution. For each well,0.5 μL of LIPOFECTAMINE reagent was diluted with 10 μL of D-MEM toprepare LIPOFECTAMINE Dilute Solution. The Plasmid Dilute Solution wasmixed with an equal volume of the LIPOFECTAMINE Dilute Solution, keptstand for 15 minutes, dispensed 20 μL per well of cell culture medium,and incubated at 37° C. under 5% CO₂ for 5 hours. Then D-MEM containing16.7% fetal bovine serum (Sanko Jun-yaku) was dispensed 100 μL per well.After 2 days culture, the cells were used for the inhibition assay ofmethyl-α-D-glucopyranoside uptake activity.

2) Inhibition Assay of methyl-α-D-glucopyranoside Uptake Activity

To Uptake Buffer consisting of 140 mM sodium chloride, 2 mM potassiumchloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM2-[2-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid, and 5 mMtris(hydroxymethyl)aminomethane (pH 7.4), was addedmethyl-α-D-glucopyranoside (α-MG) composed of its non-radiolabeled formand ¹⁴C-labeled form at 1 mM as the final concentration. For measurementof basal uptake, Basal Buffer was prepared by the addition of 140 mMcholine chloride instead of sodium chloride of the Uptake Buffer. Inorder to determine the substrate specificity among natural sugars,natural sugars were solubilized in distilled water, diluted withdistilled water into appropriate concentrations, and added to the UptakeBuffer to prepare Assay Buffer. Culture medium was discarded from thecells with transient SMINT expression, Pretreatment Buffer (Basal Bufferwithout α-MG) was added to the cells at 200 μL per well, and the cellswere incubated at 37° C. for 10 minutes. After repeating once the sameoperation, Pretreatment Buffer was removed, Assay Buffer, Uptake Bufferor Basal Buffer was added to the cells at 75 μL per well, and the cellswere incubated at 37° C. After the incubation for 1 hour, Assay Bufferwas removed, and the cells were washed twice with 150 μL per well ofWash Buffer (Basal Buffer containing 10 mM non-radiolabeled α-MG). Celllysates were prepared by addition of 75 μL per well of 0.2 mol/L sodiumhydroxide to the cells, and transferred to PicoPlate (Packard). To thecell lysates were added 150 μL per well of MicroScint 40 (Packard),mixed well, and the radioactivity was measured in a microscintillationcounter TOPCOUNT (Packard). α-MG uptake by the cells treated with eachconcentration of test compounds was calculated as relative activity tocontrol group, which is set as 100% uptake after deducting the basaluptake. A half-maximal inhibitory concentration of each test compound(IC₅₀ value) was derived from logit plot analysis. The results wereshown in FIG. 2. FIG. 2 indicates that SMINT recognizes1,5-anhydroglucitol, fructose, and mannose in addition to glucose, butnot galactose as substrates. Therefore, it is suggested that SMINT maybe 1,5-anhydroglucitol/fructose/mannose transporter expressed in thekidney and the other human tissues.

TEST EXAMPLE 3

Confirmatory Test for Inhibitory Activity on Human1,5-anhydroglucitol/fructose/mannose Transporter

1) Preparation of Cells Transiently Expressing Human SMINT

The cells were prepared according to the method described in 1) of TestExample 2.

2) Inhibition Assay of methyl-α-D-glucopyranoside Uptake Activity

To Uptake Buffer consisting of 140 mM sodium chloride, 2 mM potassiumchloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM2-[2-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid, and 5 mMtris(hydroxymethyl)aminomethane (pH 7.4), was addedmethyl-α-D-glucopyranoside (α-MG) composed of its non-radiolabeled formand ¹⁴C-labeled form at 1 mM as the final concentration. For measurementof basal uptake, Basal Buffer was prepared by the addition of 140 mMcholine chloride instead of sodium chloride of the Uptake Buffer. Inorder to determine the substrate specificity among natural sugars,natural sugars were solubilized in distilled water, diluted withdistilled water into appropriate concentrations, and added to the UptakeBuffer to prepare Assay Buffer. Culture medium was discarded from thecells with transient SMINT expression, Pretreatment Buffer (Basal Bufferwithout α-MG) was added to the cells at 200 μL per well, and the cellswere incubated at 37° C. for 10 minutes. After repeating once the sameoperation, Pretreatment Buffer was removed, Assay Buffer, Uptake Bufferor Basal Buffer was added to the cells at 75 μL per well, and the cellswere incubated at 37° C. After the incubation for 1 hour, Assay Bufferwas removed, and the cells were washed twice with 150 μL per well ofWash Buffer (Basal Buffer containing 10 mM non-radiolabeled α-MG). Celllysates were prepared by addition of 75 μL per well of 0.2 mol/L sodiumhydroxide to the cells, and transferred to PicoPlate (Packard). To thecell lysates were added 150 μL per well of MicroScint 40 (Packard),mixed well, and the radioactivity was measured in a microscintillationcounter TOPCOUNT (Packard). α-MG uptake by the cells treated with eachconcentration of test compounds was calculated as relative activity tocontrol group, which is set as 100% uptake after deducting the basaluptake. A half-maximal inhibitory concentration of each test compound(IC₅₀ value) was derived from logit plot analysis. The results wereshown in Table 30. The compounds of the invention exhibited a potentinhibitory activity on 1,5-anhydroglucitol/fructose/mannose transporter.TABLE 30 Test IC50 value compounds (nM) Example 1  92 Example 87 444Example 99 245 Example 119 296

INDUSTRIAL APPLICABILITY

The pyrazole derivatives represented by the above general formula (I) ofthe present invention, pharmaceutically acceptable salts thereof andprodrugs thereof exert an inhibitory activity in human1,5-anhydroglucitol/fructose/mannose transporter and exhibit anexcellent inhibitory activity on 1,5-anhydroglucitol/fructose/mannosetransporter found highly in the kidney and small intestine, and caninhibit blood glucose level increase by inhibiting the reabsorption atthe kidney or uptake into cells of glucose, mannose and fructose orinhibiting the sugar absorption in the small intestine. Therefore, thepresent invention can provide an agent for prevention, inhibition ofprogression or treatment of a disease associated with the excess uptakeof at least a kind of carbohydrates selected from glucose, fructose andmannose or a disease associated with hyperglycemia such as diabeticcomplications, diabetes and obesity. In addition, since the pyrazolederivatives represented by the above general formula (II) or (III) ofthe present invention and salts thereof are important as intermediatesin the production of the pyrazole derivatives represented by the abovegeneral formula (I), the compounds represented by the above generalformula (I) of the present invention can be readily prepared via suchcompounds.

1. A pyrazole derivative represented by the following general formula(I□):

wherein R¹ represents a hydrogen atom, a C₁₋₆ alkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (A), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (A), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (B), a C₂₋₉ heterocycloalkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (B); one of Q⁰ and T⁰ represents a group selected from

and the other represents a group represented by the formula:—(CH₂)_(n)—Ar wherein Ar represents a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B) or a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(B); and n represents an integral number from 0 to 2, a C₁₋₆ alkoxygroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (A), an optionally mono or di(C₁₋₆alkyl)-substituted amino group wherein the C₁₋₆ alkyl group may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), a C₂₋₉ heterocycloalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A), or a heterocycle-fused phenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B); R represents a C₃₋₈ cycloalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A), a C₆₋₁₀ aryl group which may have the same or different 1 to 3groups selected from the following substituent group (B), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (B); [substituent Group(A)]: a halogen atom, a nitro group, a cyano group, an oxo group, -G¹,—OG², —SG², —N(G²)₂, —C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G²,—S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂,—NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹; [SubstituentGroup (B)]: a halogen atom, a nitro group, a cyano group, -G¹, —OG²,—SG², —N(G²)₂, -G³OG⁴, -G³N(G⁴)₂, —C(═O)G², —C(═O)OG², —C(═O)N(G²)₂,—S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹,—OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹;in the above substituent group (A) and/or (B), G¹ represents a C₁₋₆alkyl group which may have the same or different 1 to 3 groups selectedfrom the following substituent group (C), a C₂₋₆ alkenyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₂₋₆ alkynyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), a C₃₋₈ cycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (C), a C₆₋₁₀ arylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (D), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (C), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (D); G² represents a hydrogen atom, a C₁₋₆ alkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (C), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (D), a C₂₋₉ heterocycloalkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (D), and with the proviso that G² may be the same or differentwhen there are 2 or more G² in the substituents; G³ represents a C₁₋₆alkyl group; G⁴ represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), and with the proviso that G⁴ may be the same or different whenthere are 2 or more G⁴ in the substituents; [Substituent Group (C)]: ahalogen atom, a nitro group, a cyano group, an oxo group, -G⁵, —OG⁶,—SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶,—S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶,—OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; and [Substituent Group(D)]: a halogen atom, a nitro group, a cyano group, -G⁵, —OG⁶, —SG⁶,—N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶,—S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶,—OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; in the substituent group(C) and/or (D), G⁵ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉heterocycloalkyl group or a C₁₋₉ heteroaryl group; and G⁶ represents ahydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl,a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkylgroup or a C₁₋₉ heteroaryl group, and with the proviso that G⁶ may bethe same or different when there are 2 or more G⁶ in the substituents,or a pharmaceutically acceptable salt thereof or a prodrug thereof.
 2. Apyrazole derivative as claimed in claim 1, wherein R¹ represents ahydrogen atom, a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the substituent group (A), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe substituent group (A), or a C₆₋₁₀ aryl group which may have the sameor different 1 to 3 groups selected from the substituent group (B); Q⁰represents a C₆₋₁₀ aryl group which may have the same or different 1 to3 groups selected from the substituent group (B); T⁰ represents a group:

R represents a C₆₋₁₀ aryl group which may have the same or different 1to 3 groups selected from the substituent group (B); substituent group(A) consists of a halogen atom, —OG², —SG², —N(G²)₂, —C(═O)OG²,—C(═O)N(G²)₂, —S(═O)₂OG² and —S(═O)₂N(G²)₂ in which G² represents ahydrogen atom, a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the substituent group (C); or a C₆₋₁₀ arylgroup which may have the same or different 1 to 3 groups selected fromthe substituent group (D); and substituent group (B) consists of ahalogen atom, a nitro group, a cyano group, -G¹, —OG², —SG², —C(═O)OG²in which G¹ represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the substituent group (C) or aC₆₋₁₀ aryl group which may have the same or different 1 to 3 groupsselected from the substituent group (D); and G has the same meaning asdefined above, or a pharmaceutically acceptable salt thereof or aprodrug thereof.
 3. A pyrazole derivative as claimed in claim 1, whereinone of Q⁰ and T⁰ represents a group selected from

and the other represents a group represented by the formula:—(CH₂)_(n)—Ar, or a pharmaceutically acceptable salt thereof or aprodrug thereof.
 4. A pyrazole derivative as claimed in claim 3, whereinwherein Q⁰ represents a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the substituent group (B); T⁰represents a group selected from

and R represents a C₆₋₁₀ aryl group which may have the same or different1 to 3 groups selected from the substituent group (B), or apharmaceutically acceptable salt thereof or a prodrug thereof.
 5. Apyrazole derivative as claimed in claim 4, wherein T⁰ represents agroup:

and substituent group (B) consists of a halogen atom, a nitro group, acyano group, -G¹, —OG², —SG² and —C(═O)OG² in which G¹ represents a C₁₋₆alkyl group which may have the same or different 1 to 3 groups selectedfrom the substituent group (C) or a C₆₋₁₀ aryl group which may have thesame or different 1 to 3 groups selected from the substituent group (D);and G² represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the substituent group (C)or a C₆₋₁₀ aryl group which may have the same or different 1 to 3 groupsselected from the substituent group (D), or a pharmaceuticallyacceptable salt thereof or a prodrug thereof.
 6. A pyrazole derivativeas claimed in claim 1, wherein one of Q⁰ and T⁰ represents a groupselected from

and the other represents a C₁₋₆ alkoxy group which may have the same ordifferent 1 to 3 groups selected from the substituent group (A), anoptionally mono or di(C₁₋₆ alkyl)-substituted amino group in which theC₁₋₆ alkyl group may have the same or different 1 to 3 groups selectedfrom the substituent group (A), or a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from thesubstituent group (A), or a pharmaceutically acceptable salt thereof ora prodrug thereof.
 7. A pyrazole derivative as claimed in claim 6,wherein Q⁰ represents an optionally mono or di(C₁₋₆ alkyl)-substitutedamino group in which the C₁₋₆ alkyl group may have the same or different1 to 3 groups selected from the substituent group (A), or a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the substituent group (A); and T⁰ represents agroup selected from

or a pharmaceutically acceptable salt thereof or a prodrug thereof.
 8. Apyrazole derivative as claimed in claim 1, wherein one of Q⁰ and T⁰represents a group selected from

and the other represents a heterocycle-fused phenyl group which may havethe same or different 1 to 3 groups selected from the substituent group(B), or a pharmaceutically acceptable salt thereof or a prodrug thereof.9. A pyrazole derivative as claimed in claim 8, wherein Q⁰ represents aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the substituent group (B); and T⁰ represents agroup selected from

or a pharmaceutically acceptable-salt thereof or a prodrug thereof. 10.A pharmaceutical composition comprising as an active ingredient apyrazole derivative as claimed in claim 1, or a pharmaceuticallyacceptable salt thereof or a prodrug thereof.
 11. An inhibitor of1,5-anhydroglucitol/fructose/mannose transporter comprising as an activeingredient a pyrazole derivative represented by the following generalformula (I):

wherein R¹ represents a hydrogen atom, a C₁₋₆ alkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (A), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (A), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (B), a C₂₋₉ heterocycloalkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (B); one of Q and T represents a group selected from

and the other represents a group represented by the formula:—(CH₂)_(n)—Ar wherein Ar represents a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (B) or a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(B); and n represents an integral number from 0 to 2, a C₁₋₆ alkyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (A), a C₁₋₆ alkoxy group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A), an optionally mono or di(C₁₋₆ alkyl)-substituted amino groupwherein the C₁₋₆ alkyl group may have the same or different 1 to 3groups selected from the following substituent group (A), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the following substituent group (B); R representsa C₃₋₈ cycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A), a C₆₋₁₀ arylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (B), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (A), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (B); [Substituent Group (A)]: a halogen atom, a nitro group, acyano group, an oxo group, -G¹, —OG², —SG², —N(G²)₂, —C(═O)G²,—C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹,—OC(═O)G¹, —OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and—C(═O)NHS(═O)₂G¹; [Substituent Group (B)]: a halogen atom, a nitrogroup, a cyano group, -G¹, —OG², —SG², —N(G²)₂, -G³OG⁴, -G³N(G⁴)₂,—C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂,—S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹and —C(═O)NHS(═O)₂G¹; in the above substituent group (A) and/or (B), G¹represents a C₁₋₆ alkyl group which may have the same or different 1 to3 groups selected from the following substituent group (C), a C₂₋₆alkenyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₂₋₆ alkynyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C), a C₃₋₈ cycloalkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D), a C₂₋₉ heterocycloalkyl group which may have the same or different1 to 3 groups selected from the following substituent group (C), or aC₁₋₉ heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (D); G² represents ahydrogen atom, a C₁₋₆ alkyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), a C₂₋₆alkenyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₂₋₆ alkynyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C), a C₃₋₈ cycloalkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D), a C₂₋₉ heterocycloalkyl group which have the same or different 1 to3 groups selected from the following substituent group (C), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (D), and with the provisothat G² may be the same or different when there are 2 or more G² in thesubstituents; G³ represents a C₁₋₆ alkyl group; G⁴ represents a C₁₋₆alkyl group which may have the same or different 1 to 3 groups selectedfrom the following substituent group (C), and with the proviso that G⁴may be the same or different when there are 2 or more G⁴ in thesubstituents; [Substituent Group (C)]: a halogen atom, a nitro group, acyano group, an oxo group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶,—C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂, —S(═O)G⁵,—OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and—C(═)NHS(═O)₂G⁵; and Substituent Group (D)]: a halogen atom, a nitrogroup, a cyano group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶,—C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵,—OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵;in the substituent group (C) and/or (D), G⁵ represents a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, aC₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroarylgroup; and G⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ arylgroup, a C₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroaryl group, andwith the proviso that G⁶ may be the same or different when there are 2or more G⁶ in the substituents, or a pharmaceutically acceptable saltthereof or a prodrug thereof.
 12. An inhibitor of1,5-anhydroglucitol/fructose/mannose transporter comprising as an activeingredient a pyrazole derivative as claimed in claim 1, or apharmaceutically acceptable salt thereof or a prodrug thereof.
 13. Anagent as claimed in claim 11, which is an agent for the prevention,inhibition of progression or treatment of a disease associated with theexcess uptake of at least a kind of carbohydrates selected from glucose,fructose and mannose.
 14. An agent for the prevention, inhibition ofprogression or treatment of a disease associated with the excess uptakeof at least a kind of carbohydrates selected from glucose, fructose andmannose comprising as an active ingredient a pyrazole derivative asclaimed in claim 1, or a pharmaceutically acceptable salt thereof or aprodrug thereof.
 15. An agent as claimed in claim 13, wherein thedisease associated with the excess uptake of at least a kind ofcarbohydrates selected from glucose, fructose and mannose is diabeticcomplications.
 16. An agent as claimed in claim 14, wherein the diseaseassociated with the excess uptake of at least a kind of carbohydratesselected from glucose, fructose and mannose is diabetic complications.17. An agent as claimed in claim 15, wherein the diabetic complicationsis diabetic nephropathy.
 18. An agent as claimed in claim 16, whereinthe diabetic complications is diabetic nephropathy.
 19. An agent asclaimed in claim 13, wherein the disease associated with the excessuptake of at least a kind of carbohydrates selected from glucose,fructose and mannose is diabetes.
 20. An agent as claimed in claim 14,wherein the disease associated with the excess uptake of at least a kindof carbohydrates selected from glucose, fructose and mannose isdiabetes.
 21. A pharmaceutical combination which comprises (component a)a pyrazole derivative as claimed in claim 1, or a pharmaceuticallyacceptable salt thereof or a prodrug thereof, and (component b) at leastone member selected from the group consisting of an insulin sensitivityenhancer, a glucose absorption inhibitor, a biguanide, an insulinsecretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, aglucagon receptor antagonist, an insulin receptor kinase stimulant, atripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor,a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylaseinhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphataseinhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesisinhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor,glucagon-like peptide-1, a glucagon-like peptide-1 analogue, aglucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylinagonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethylglutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.
 22. A pyrazole derivative represented by the followinggeneral formula (IIα):

wherein R^(1A) represents a hydrogen atom, a C₁₋₆ alkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A1), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A1), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (B1), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (A1), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (B1); one of Q^(A0) and T^(A0) represents a group selected from

having protective group(s), and the other represents a group representedby the formula: —(CH₂)_(n)—Ar wherein Ar represents a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (B1) or a C₁₋₉ heteroaryl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (B1); and n represents an integral number from 0 to 2,a C₁₋₆ alkoxy group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), an optionally monoor di(C₁₋₆ alkyl)-substituted amino group wherein the C₁₋₆ alkyl groupmay have the same or different 1 to 3 groups selected from the followingsubstituent group (A1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (A1), or a heterocycle-fused phenyl group which may have the sameor different 1 to 3 groups selected from the following substituent group(B1); R^(A) represents a C₃₋₈ cycloalkyl group which may have the sameor different 1 to 3 groups selected from the following substituent group(A1), a C₆₋₁₀ aryl group which may have the same or different 1 to 3groups selected from the following substituent group (B1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (B1); [Substituent Group(A1)]: a halogen atom, a nitro group, a cyano group, an oxo group,-G^(1A), —OG^(2B), —SG^(2B), —N(G^(2B))₂, —C(═O)G^(2A), —C(═O)OG^(2B),—C(═O)N(G^(2B))₂, —S(═O)₂G^(2A), —S(═O)₂OG^(2A), —S(═O)₂N(G^(2B))₂,—S(═O)G^(1A), —OC(═O)G^(1A), —OC(═O)N(G^(2B))₂, —NHC(═O)G^(2A),—OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and —C(═O)NHS(═O)₂G^(1A); [SubstituentGroup (B1)]: a halogen atom, a nitro group, a cyano group, -G^(1A),—OG^(2B), —SG^(2B), —N(G^(2B))₂, -G³OG^(4A), -G³N(G^(4A))₂,—C(═O)G^(2A), —C(═O)OG^(2B), —C(═O)N(G^(2B))₂, —S(═O)₂G^(2A),—S(═O)₂OG^(2A), —S(═O)₂N(G^(2B))₂, —S(═O)G^(1A), —OC(═O)G^(1A),—OC(═O)N(G^(2B))₂, —NHC(═O)G^(2A), —OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and—C(═O)NHS(═O)₂G^(1A); in the above substituent group (A1) and/or (B1),G^(1A) represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₂₋₆ alkenyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D1); G^(2A) represents a hydrogen atom, a C₁₋₆ alkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C1), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (D1), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (C1), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (D1); G^(2B) represents a protective group, a hydrogen atom, aC₁₋₆ alkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₂₋₆ alkenyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C1), a C₂₋₆ alkynyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C1), a C₃₋₈ cycloalkyl group which may have the sameor different 1 to 3 groups selected from the following substituent group(C1), a C₆₋₁₀ aryl group which may have the same or different 1 to 3groups selected from the following substituent group (D1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (D1), and with the provisothat G^(2B) may be the same or different when there are 2 or more G^(2B)in the substituents; G³ represents a C₁₋₆ alkyl group; G^(4A) representsa C₁₋₆ alkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), and with the provisothat G^(4A) may be the same or different when there are 2 or more G^(4A)in the substituents; [Substituent Group (C1)]: a halogen atom, a nitrogroup, a cyano group, -G⁵, —OG^(6A), —SG^(6A), —N(G^(6A))₂, —C(═O)G⁶,—C(═O)OG^(6A), —C(═O)N(G^(6A))₂, —S(═O)₂G⁶, —S(═O)₂OG⁶,—S(═O)₂N(G^(6A))₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G^(6A))₂, —NHC(═O)G⁶,—OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; and [Substituent Group(D1)]: a halogen atom, a nitro group, a cyano group, -G⁵, —OG^(6A),—SG^(6A), —N(G^(6A))₂, —C(═O)G⁶, —C(═O)OG^(6A), —C(═O)N(G^(6A))₂,—S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G^(6A))₂, —S(═O)G⁵, —OC(═O)G⁵,—OC(═O)N(G^(6A))₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and—C(═O)NHS(═O)₂G⁵; in the substituent group (C1) and/or (D1), G⁵represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl, aC₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl groupor a C₁₋₉ heteroaryl group; G⁶ represents a hydrogen atom, a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, aC₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroarylgroup; and G^(6A) represents a protective group, a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl, a C₃₋₈ cycloalkylgroup, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉heteroaryl group, and with the proviso that G^(6A) may be the same ordifferent when there are 2 or more G^(6A) in the substituents, or apharmaceutically acceptable salt thereof.
 23. A pyrazole derivativerepresented by the following general formula (IIIα):

wherein R^(1A) represents a hydrogen atom, a C₁₋₆ alkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A1), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A1), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (A1), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (B1), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (A1), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (B1); one of Q^(B0) and T^(B0) represents a hydroxy group, and theother represents a group represented by the formula: —(CH₂)_(n)—Ar^(A)wherein Ar^(A) represents a C₆₋₁₀ aryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B1) or a C₁₋₉ heteroaryl group which may have the same or different 1to 3 groups selected from the following substituent group (B1); and nrepresents an integral number from 0 to 2, a C₁₋₆ alkoxy group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (A1), an optionally mono or di(C₁₋₆ alkyl)-substitutedamino group wherein the C₁₋₆ alkyl group may have the same or different1 to 3 groups selected from the following substituent group (A1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or aheterocycle-fused phenyl group which may have the same or different 1 to3 groups selected from the following substituent group (B1); R^(A)represents a C₃₋₈ cycloalkyl group which may have the same or different1 to 3 groups selected from the following substituent group (A1), aC₆₋₁₀ aryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (B1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (A1), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (B1); [Substituent Group(A1)]: a halogen atom, a nitro group, a cyano group, an oxo group,-G^(1A), —OG^(2B), —SG^(2B), —N(G^(2B))₂, —C(═O)G^(2A), —C(═O)OG^(2B),—C(═O)N(G^(2B))₂, —S(═O)₂G^(2A), —S(═O)₂OG^(2A), —S(═O)₂N(G^(2B))₂,—S(═O)G^(1A), —OC(═O)G^(1A), —OC(═O)N(G^(2B))₂, —NHC(═O)G^(2A),—OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and —C(═O)NHS(═O)₂G^(1A); [SubstituentGroup (B1)]: a halogen atom, a nitro group, a cyano group, -G^(1A),—OG^(2B), —SG^(2B), —N(G^(2B))₂, -G³OG^(4A), -G³N(G^(4A))₂,—C(═O)G^(2A), —C(═O)OG^(2B), —C(═O)N(G^(2B))₂, —S(═O)₂G^(2A),—S(═I)₂OG^(2A), —S(═O)₂N(G^(2B))₂, —S(═O)G^(1A), —OC(═O)G^(1A),—OC(═O)N(G^(2B))₂, —NHC(═O)G^(2A), —OS(═O)₂G^(1A), —NHS(═O)₂G^(1A) and—C(═O)NHS(═O)₂G^(1A); in the above substituent group (A1) and/or (B1),G^(1A) represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₂₋₆ alkenyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C1), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D1), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C1), or a C₁₋₉ heteroaryl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D1); G^(2A) represents a hydrogen atom, a C₁₋₆ alkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C1), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C1), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (D1), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (C1), or a C₁₋₉ heteroaryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (D1); G^(2B) represents a protective group, a hydrogen atom, aC₁₋₆ alkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), a C₂₋₆ alkenyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (C1), a C₂₋₆ alkynyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C1), a C₃₋₈ cycloalkyl group which may have the sameor different 1 to 3 groups selected from the following substituent group(C1), a C₆₋₁₀ aryl group which may have the same or different 1 to 3groups selected from the following substituent group (D1), a C₂₋₉heterocycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (C1), or a C₁₋₉heteroaryl group which may have the same or different 1 to 3 groupsselected from the following substituent group (D1), and with the provisothat G^(2B) may be the same or different when there are 2 or more G^(2B)in the substituents; G³ represents a C₁₋₆ alkyl group; G^(4A) representsa C₁₋₆ alkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C1), and with the provisothat G^(4A) may be the same or different when there are 2 or more G^(4A)in the substituents; [Substituent Group (C1)]: a halogen atom, a nitrogroup, a cyano group, an oxo group, -G⁵, —OG^(6A), —SG^(6A),—N(G^(6A))₂, —C(═O)G⁶, —C(═O)OG^(6A), —C(═O)N(G^(6A))₂, —S(═O)₂G⁶,—S(═O)₂OG^(g), —S(═O)₂N(G^(6A))₂, —S(═O)G⁵, —OC(═O)G⁵,—OC(═O)N(G^(6A))₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and—C(═O)NHS(═O)₂G⁵; and [Substituent Group (D1)]: a halogen atom, a nitrogroup, a cyano group, -G⁵, —OG^(6A), —SG^(6A), —N(G^(6A))₂, —C(═O)G⁶,—C(═O)OG^(6A), —C(═O)N(G^(6A))₂, —S(═O)₂G⁶, —S(═O)₂G⁶,—S(═O)₂N(G^(6A))₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G^(6A))₂, —NHC(═O)G⁶,—OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; in the substituent group(C1) and/or (D1), G⁵ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, aC₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroaryl group; G⁶ represents ahydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl,a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkylgroup or a C₁₋₉ heteroaryl group; and G^(6A) represents a protectivegroup, a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉heterocycloalkyl group or a C₁₋₉ heteroaryl group, and with the provisothat G^(6A) may be the same or different when there are 2 or more G^(6A)in the substituents, or a pharmaceutically acceptable salt thereof.